U.S. patent number 5,182,403 [Application Number 07/872,557] was granted by the patent office on 1993-01-26 for substituted 3(5'indazolyl) oxazolidin-2-ones.
This patent grant is currently assigned to The Upjohn Company. Invention is credited to Steven J. Brickner.
United States Patent |
5,182,403 |
Brickner |
January 26, 1993 |
**Please see images for:
( Certificate of Correction ) ** |
Substituted 3(5'indazolyl) oxazolidin-2-ones
Abstract
The present invention relates to 3 indazol substituted 5 Beta
amidomethyloxazolidin-2ones, useful as antibacterial agents and to
intermediates for their production.
Inventors: |
Brickner; Steven J. (Portage,
MI) |
Assignee: |
The Upjohn Company (Kalamazoo,
MI)
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Family
ID: |
27540208 |
Appl.
No.: |
07/872,557 |
Filed: |
April 23, 1992 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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655419 |
Feb 20, 1991 |
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324942 |
Mar 17, 1989 |
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253850 |
Oct 5, 1988 |
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244988 |
Sep 15, 1988 |
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Current U.S.
Class: |
548/231; 546/196;
546/199; 548/229; 548/232; 548/257; 548/260; 548/304.4; 548/361.1;
548/362.5; 548/452; 548/465; 548/483 |
Current CPC
Class: |
C07D
263/20 (20130101); C07D 413/04 (20130101) |
Current International
Class: |
C07D
413/00 (20060101); C07D 263/00 (20060101); C07D
263/20 (20060101); C07D 413/04 (20060101); C07D
263/14 () |
Field of
Search: |
;548/231,229,232 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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892270 |
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Aug 1982 |
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BE |
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127902 |
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Jun 1984 |
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EP |
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184170 |
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Nov 1985 |
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EP |
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Other References
Ioli et al., Chem. Abstr. vol. 103 entry 160009b(1985). .
Belcsteins Handbuch vol. 145, Aufl XXVII. .
Slee, A. M. et al., Oxazolidinones, a New Class of Synthetic
Antibacterial Agnets: In Vitro and In Vivo Activities of DuP 105
and DuP 721, Antimicrobial Agnets and chemotherapy, vol. 31 (No.
11): 1791-1797 (Nov. 1987)..
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Primary Examiner: Daus; Donald G.
Attorney, Agent or Firm: Stein; Bruce
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATIONS
The present patent application is a divisional of U.S. patent
application Ser. No. 07/655,419, pending, filed Feb. 20, 1991 which
was the national phase application of international application
PCT/US89/03548, filed Aug. 22, 1989, which designated the United
States; which was a continuation-in-part of U.S. applications, Ser.
No. 07/324,942, filed Mar. 17, 1989 (abandoned Sep. 20, 1989), Ser.
No. 07/253,850, filed Oct. 5, 1989 (abandoned Sep. 14, 1989) and
Ser. No. 07/244,988, filed Sep. 15, 1988 (abandoned Sep. 14, 1989).
Claims
I claim:
1. A 3-(nitrogen
substituted)phenyl-5.beta.-amidomethyl)oxazolidin-2-ones of formula
(LV)
where
(I) R.sub.1 is --H, C.sub.1 -C.sub.4 alkyl, cyclopropyl,
--CHCl.sub.2, --CCl.sub.3, --O--R.sub.1-3 where R.sub.1-3 is
C.sub.1 -C.sub.4 alkyl, --CH.sub.2 OH, --CH.sub.2 OR.sub.1-5 where
R.sub.1-5 is C.sub.1 -C.sub.4 alkyl or --CO--R.sub.1-6 where
R.sub.1-6 is C.sub.1 -C.sub.4 alkyl or --.phi.;
(II) two of R.sub.2, R.sub.3 and R.sub.4 are --H and the other of
R.sub.2, R.sub.3 and R.sub.4 is --H, --F, --Cl, C.sub.1 -C.sub.6
alkyl, --C.tbd.N,
(IIIA) where W.sub.1 and W.sub.2 taken together are
where R.sub.5 is --H, C.sub.1 -C.sub.12 alkyl, --CH.sub.2 .phi.,
--CH.sub.2 CH.sub.2 --.phi., C.sub.3 -C.sub.7 cycloalkyl, C.sub.2
-C.sub.12 alkynyl containing 1 triple bond, --CHO, --CO--R.sub.5-1
where R.sub.5-1 is
(A) C.sub.1 -C.sub.6 alkyl optionally substituted with 1 13
O--CH.sub.3, --COOH, or 1-3 --Cl,
(B) C.sub.3 -C.sub.7 cycloalkyl,
(D) --.phi.optionally substituted with 1-3 --F, --Cl, C.sub.1
-C.sub.6 alkyl, --C.tbd.N,
--CO--O--R.sub.5-8 where R.sub.5-8 is C.sub.1 -C.sub.4 alkyl or
--.phi. optionally substituted with 1 or 2 --F, --Cl, C.sub.1
-C.sub.6 alkyl, --O--CH.sub.3, --C.tbd.N,
--CO--N(R.sub.5-9).sub.2 where R.sub.5-9 is --H or R.sub.5-8 as
defined above --CO--CH.sub.2 CN, --CO--CH.sub.2 --OH,
--CO--CH.sub.2 O--.phi. where --.phi. is optionally substituted
with 1-3 --O--CH.sub.3,
--CO--CH.sub.2 --O--R.sub.5-10 where R.sub.5-10 is C.sub.1 -C.sub.6
alkyl, --.phi. optionally substituted with 1-3 --O--CH.sub.3,
--CO--R.sub.5-11 where R.sub.5-11 is C.sub.1 -C.sub.6 alkyl,
--.phi. optionally substituted with 1-4--F, 1-3 --Cl, 1
--OCH.sub.3, --SO.sub.2 CH.sub.3, --SO.sub.2 --.phi.,
and R.sub.6 is --H and C.sub.1 -C.sub.3 alkyl; and pharmaceutically
acceptable salts thereof.
2. A 3-(nitrogen
substituted)phenyl-5.beta.-(amidomethyl)oxazolidin-2-one (LV)
according to claim 1 where R.sub.1 --H, C.sub.1 -C.sub.4 alkyl,
C.sub.3 cycloalkyl, --OCH.sub.3 and --CHCl.sub.2 and where R.sub.5
is selected from the group consisting of --CH.sub.3, --CH.sub.2
--C.tbd.CH, --CHO, --CO--R.sub.5-1 where R.sub.5-1 is --CH.sub.3,
--C.sub.2 H.sub.5, --CH(CH.sub.3).sub.2, --CHCl.sub.2, --CH.sub.2
O--CH.sub.3 and cyclopentyl.
3. A 3-(nitrogen
substituted)phenyl-5.beta.-(amidomethyl)oxazolidin-2-one (LV)
according to claim 1 where R.sub.2, R.sub.3 and R.sub.4 are all
--H.
4. A 3-(nitrogen
substituted)phenyl-5.beta.-amidomethyl)oxazolidin-2-one (LV)
according to claim 1 where W.sub.1 and W.sub.2 taken together are
--NR.sub.5 --N.dbd.CR.sub.5 -- which is a indazolyloxazolidin-2-one
(XXXII).
5. An indazolyloxazolidin-2-one (XXXII) according to claim 4 which
is
3-5'-(1-acetylindazolyl)]-5.beta.-(acetamidomethyl)oxazolidin-2-one,
3-(5'-indazolyl)-5.beta.-(acetamidomethyl)oxazolidin-2-one,
3-[5'-(1-ethylindazolyl)]-5.beta.-(acetamidomethyl)oxazolidin-2-one
and
[3-5'-(1-n-propylindazolyl)]-5.beta.-(acetamidomethyl)oxazolidin-2-one.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to 5'-indolinyloxazolidinones (XI),
3-(fused-ring substituted)phenyl-5.beta.-amidomethyloxazolidinones
(XXI), 3-(nitrogen
substituted)phenyl-5.beta.-amidomethyloxazolidinones (LV) which are
useful as antibacterial agents.
2. Description of the Related Art
U.S. Pat. No. 4,128,654 discloses
5-halomethylphenyl-2-oxazolidinones which are useful in controlling
fungal and bacterial diseases of plants.
U.S. Pat. No. 4,250,318 discloses 3-substituted
phenyl-5-hydroxymethyloxazolidinones having antidepressive
utility.
U.S. Pat. No. Re. 29,607 discloses 3-substituted
phenyl-5-hydroxymethyloxazolidinones having antidepressive,
tranquilizing and sedative utility.
U.S. Pat. No. 4,340,606 discloses
3-(p-alkylsulfonyl)phenyl-5-(hydroxymethyl or
acyloxymethyl)oxazolidinones having antibacterial activity in
mammals.
Belgium Patent 892,270 discloses 3-(arylalkyl, arylalkenyl or
arylacetylenic substituted)phenyl)-5-(aminomethyl)oxazolidinones
which are inhibitors of monoamine oxidase.
U.S. Pat. No. 4,461,773 discloses 3-substituted
phenyl-5-hydroxymethyloxazolidinones which have antibacterial
activity.
European Patent Publications 127,902 and 184,170 disclose
3-substituted phenyl-5-amidomethyloxazolidinones which have
antibacterial utility.
Antimicrobial Agents and Chemotherapy 1791 (1987) discusses
compounds disclosed in European Patent Publications 127,902 and
184,170, discussed above, and compares these new compounds with
known antibiotics.
U.S. Pat. No. 4,705,799 discloses aminomethyloxooxazolidinyl
benzene derivatives including sulfides, sulfoxides, sulfones and
sulfonamides which possess antibacterial activity.
U.S. Pat. No. 4,801,600 (WANG) discloses 6'-indolinyloxazolidinones
(where the indolinyl nitrogen is meta to the oxazolidinone
nitrogen) both generically, see formula (I) where "X" is NR.sub.6
and specifically see Example 13. The indolinyloxazolidinones of the
present invention are 5'-indolinyloxazolidinones (where the
indolinyl nitrogen is para to the oxazolidinone nitrogen). Further,
WANG discloses aminomethyloxooxazolidinyl cycloalkylbenzene
derivatives including cycloalkyl-, alkanone-, hydroxycycloalkyl-,
oxime-, amine- and other phenyloxazolidinones which possess
antibacterial activity. More particularly, WANG discloses alkanone
or indanone oxazolidinones generally, see formula (I) where R.sub.1
and R.sub.2 taken together are .dbd.O and specifically, see
Examples 16, 26 and 30. All the indanoneoxazolidinones disclosed by
WANG require the ketone (--CO--) to be attached directly to the
phenyl ring in a position para to the oxazolidinone nitrogen. The
indanoneoxazolidinones (XXIB) of the present invention differ from
those of WANG. WANG also discloses oximinooxazolidinones, see
Example 21 as well as the generic disclosure for R.sub.1 and
R.sub.2 taken together to be .dbd.NOH.
SUMMARY OF THE INVENTION
Discloses are 3-(nitrogen
substituted)phenyl-5.beta.-(amidomethyl)oxazolidin-2-ones of
formula (LV) where
(I) R.sub.1 is --H,
C.sub.1 -C.sub.4 alkyl,
cyclopropyl,
--CHCl.sub.2, --CCl.sub.3,
--O--R.sub.1-3 where R.sub.1-3 is C.sub.1 -C.sub.4 alkyl,
--CH.sub.2 --OH,
--CH.sub.2 --OR.sub.1-5 where R.sub.1-5 is C.sub.1 -C.sub.4 alkyl
or --CO--R.sub.1-6 where R.sub.1-6 is C.sub.1 -C.sub.4 alkyl or
--.phi.;
(II) two of R.sub.2, R.sub.3 and R.sub.4 are --H and the other of
R.sub.2, R.sub.3 and R.sub.4 is
--H,
--F, --Cl,
C.sub.1 -C.sub.6 alkyl,
--C.tbd.N,
(IIIA) where W.sub.1 and W.sub.2 taken together are
where R.sub.5 is --H, C.sub.1 -C.sub.12 alkyl, --CH.sub.2 --.phi.,
--CH.sub.2 CH.sub.2 --.phi., C.sub.3 -C.sub.7 cycloalkyl, C.sub.2
-C.sub.12 alkynyl containing 1 triple bond, --CHO, --CO--R.sub.5-1
where R.sub.5-1 is
(A) C.sub.1 -C.sub.6 alkyl optionally substituted with 1
--O--CH.sub.3, --COOH, or 1-3 --Cl,
(B) C.sub.3 -C.sub.7 cycloalkyl,
(D) --.phi. optionally substituted with 1-3 --F, --Cl, C.sub.1
-C.sub.6 alkyl, --C.tbd.N,
--CO--O--R.sub.5-8 where R.sub.5-8 is C.sub.1 -C.sub.4 alkyl or
--.phi. optionally substituted with 1 or 2
--F, --Cl,
C.sub.1 -C.sub.6 alkyl,
--O--CH.sub.3,
--C.tbd.N,
--CO--N(R.sub.5-9).sub.2 where R.sub.5-9 is --H or R.sub.5-8 as
defined above
--CO--CH.sub.2 --CN,
--CO--CH.sub.2 --OH,
--CO--CH.sub.2 --O--.phi. where --.phi. is optionally substituted
with 1-3 --O--CH.sub.3,
--CO--CH.sub.2 --O--R.sub.5-10 where R.sub.5-10 is
C.sub.1 -C.sub.6 alkyl,
--.phi. optionally substituted with 1-3 --O--CH.sub.3,
--CO--R.sub.5-11 where R.sub.5-11 is C.sub.1 -C.sub.6 alkyl,
--.phi. optionally substituted with 1-4 --F, 1-3 --Cl, 1
--OCH.sub.3,
--SO.sub.2 --CH.sub.3,
--SO.sub.2 --.phi.,
and R.sub.6 is --H and C.sub.1 -C.sub.3 alkyl; and pharmaceutically
acceptable salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
The 5'-indolinyloxazolidin-2-ones (XI) are prepared starting with
the corresponding 5-nitroindolines (I). It is preferred that
R.sub.2, R.sub.3 and R.sub.4 all be --H. The indolinyl nitrogen of
the 5-nitroindolines (I) is protected to produce the corresponding
protected 5-nitroindolines (II). Suitable protecting agents,
X.sub.1, include t-butyloxycarbonyl (BOC), acetyl,
--CO--O--CH.sub.2 --.phi. and --CO--O--(CH.sub.2).sub.2
--Si(CH.sub.3).sub.3. It is preferred that X.sub.1 be
t-butyloxycarbonyl. Next, the nitro group of the protected
5-nitroindolines (II) is reduced with hydrogen and an appropriate
catalyst such as palladium on carbon to the corresponding protected
5-aminoindolines (III). Acylation of the free unprotected 5-amino
group of the 1-protected 5-aminoindolines (III) with a
carbobenzyloxy (CBZ) group gives the urethanes (IV). The urethanes
(IV) are then reacted with Br--CH.sub.2 -- CH.dbd.CH.sub.2 in THF
and a base forming the N-allyl-N-CBZ compounds (V). Suitable bases
include sodium hydride, sodium methoxide, potassium tertiary
butoxide and lithium diisopropylamide; preferred is sodium hydride.
The N-allyl-N-CBZ compounds (V) are cyclized to form the
oxazolidinone nucleus by reaction with an electrophilic agent.
Suitable electrophilic agents include bromine and iodine; iodine in
chloroform is preferred. The oxazolidinone nucleus formed is the
protected 5-iodomethyloxazolidin-2-one (VI). Following formation of
the oxazolidinone ring, the desired side chain at the 5-position is
formed by reacting the protected 5-iodomethyl oxazolidinones (VI)
with an azide to form the protected azides (VII). The protected
azides (VII) are reduced with hydrogen in the presence of a
catalyst such as palladium or by Po.sub.3 or H.sub.2 S or other
methods known to those skilled in the art to give racemic protected
5-aminomethyloxazolidin-2-ones (VIII). The racemic compounds can be
resolved at the aminomethyloxazolidinone (VIII) stage using methods
known to those skilled in the art, see for example, Optical
Resolution Procedures for Chemical Compounds, Vol. 1,: Amines and
Related Compounds, Paul Newman, Optical Resolution Information
Center, Manhattan College, Riverdale, N.Y., 10471, 1978. For
example, treatment of the d,l-aminomethyloxazolidinone (VIII)
mixture with an optically active acid such as (+)-tartaric acid or
alternatively with (-)-tartaric acid, would yield a mixture of
diastereomeric salts, which can be separated most conviently by
fractional crystallization to give a salt containing only one
enantiomer of the racemic mixture. Other suitable optically active
acids include, (-) dibenzoyltartaric acid, (+)-camphoric acid, (+)-
and (-)-malic acid and (+)-camphor-10-sulfonic acid. By reacting
the diastereomeric salt with a base one obtains the enantiomer as
the free compound. These compounds are then acylated to produce the
protected 5'-indolinyloxazolidin-2-ones (IX) containing the desired
R.sub.1 group. It is preferred that R.sub.1 is H, C.sub.1 -C.sub.6
alkyl, C.sub.3 -C.sub.6 cycloalkyl, --OCH.sub.3 and --CHCl.sub.2 ;
it is more preferred that R.sub.1 is --CH.sub.3. Acid hydrolysis of
the (BOC) protected 5'-indolinyloxazolidi-2-nones (IX) produces the
unprotected 5'-indolinyloxazolidin-2-ones (X) which are then
N-acylated or N-alkylated, if necessary, with the desired R.sub.5
group, either as the acid halide, anhydride, or through a reductive
alkylation sequence to produce the desired
5'-indolinyloxazolidin-2-ones (XI). The CBZ protecting group is
removed by hydrogen with palladium on carbon and the
--CO--O--(CH.sub.2).sub.2 --Si(CH.sub.3).sub.3 is removed by
tetra-butylammonium fluoride, see J. Chem. Soc. Chem. Commun., 358
(1970). For the 5'-indolinyloxazolidin-2-ones (XI), it is preferred
that R.sub.5 is --CH.sub.3, --CH.sub.2 --CH.dbd.CH.sub.2,
--CH.sub.2 --C.tbd.CH, --CHO, --CO--R.sub.5-1 where R.sub.5-1 is
--CH.sub.3, --C.sub.2 H.sub.5, --CH(CH.sub.3).sub.2, --CH.sub.2 Cl,
--CHCl.sub.2, --CH.sub.2 --OH, --CH.sub.2 --O--CH.sub.3, 2-thienyl
and cyclopropyl. It is more preferred that R.sub.5 is --CH.sub.3,
--CH.sub.2 --CH.dbd.CH.sub.2, --CHO, --CO--R.sub.5-1 where
R.sub.5-1 is --CH.sub.3, --C.sub. 2 H.sub.5, --CHCl.sub.2,
--CH.sub.2 --OH and 2-thienyl.
The 3-(fused-ring
substituted)phenyl-5.beta.-amidomethyloxazolidin-2-ones (XXI) are
prepared by methods known to those skilled in the art from known
starting compounds. See, for example, European Patent Publications
127,902 and 184,170; Antimicrobial Agents and Chemotherapy 1791
(1987) and Tetrahedron 43, 2505 (1987).
The 3-(fused-ring
substituted)phenyl-5.beta.-amidomethyloxazolidin-2-ones (XXI) of
the present invention include the fused
alkanonephenyloxazolidinones (B), the fused
cycloalkenylphenyloxazolidinones (D), and the fused
oximinocycloalkylphenyl-oxazolidinones (E), see CHART C. It is
preferred that the 3-(fused-ring
substituted)phenyl-5.beta.-amidomethyloxazolidinones (XXI) are the
fused alkanenephenyloxazolidinones (B) and the fused
oximinocycloalkylphenyloxazolidinones (E). It is more preferred
that the 3-(fused-ring
substituted)phenyl-5.beta.-amidomethyloxazolidin-2-ones (XXI) are
the fused alkanonephenyloxazolidin-2-ones (B).
The oxazolidinone nucleus is formed by starting with an
appropriately substituted aniline (XV) containing the desired
R.sub.2 /R.sub.3 /R.sub.4 moiety (see CHART C) or one which can
readily be transformed to the desired moiety. The oxazolidinone
ring system is synthesized after protecting the aniline (XV)
nitrogen with a carbobenzyloxy (CBZ) group. Acylation of the
aniline (XV) nitrogen atom gives the urethane (XVI). The urethane
(XVI) is then reacted with Br--CH.sub.2 --CH.dbd.CH.sub.2 in THF
and a base forming an N-allyl-N-CBZ compound (XVII). Suitable bases
include sodium hydride, sodium methoxide, potassium tertiary
butoxide and lithium diisopropylamide; preferred is sodium hydride.
The N-allyl-N-CBZ compound (XVII) is cyclized to form the
oxazolidinone nucleus by reaction with an electrophilic agent.
Suitable electrophilic agents include bromine and iodine; iodine in
chloroform is preferred. The oxazolidinone nucleus formed is the
5-iodomethyloxazolidin-2-one (XVIII). When the phenyl substituent
contains a chiral center then the oxazolidinone ring has two
different substituents at the C.sub.5 position and therefore
produces two diastereomers. These can be separated by
crystallization or chromatography. Following formation of the
oxazolidinone ring, the desired side chain at the 5-position is
formed by reacting the iodomethyloxazolidin-2-one (XVIII) with an
azide to form the azide (XIX). The azide is reduced with hydrogen
in the presence of a catalyst such as palladium or by Po.sub.3 or
H.sub.2 S or other methods known to those skilled in the art to
give the 5-aminomethyl oxazolidinone as the N-appropriately
substituted-3-phenyl-5-aminomethyloxazolidin-2-one (XX). This
compound is then acylated to give the desired R.sub.1 group. It is
preferred that R.sub.1 is --H, C.sub.1 -C.sub.6 alkyl, C.sub.3
-C.sub.6 cycloalkyl, --OCH.sub.3, --CHCl.sub.2 and --CH.sub.2 Cl;
it is more preferred that R.sub.1 is --CH.sub.3.
This process is operative regardless of whether the 3-fused- ring
substituted)phenyl-5-amidomethyloxazolidin-2-one (XXI) has a five
or six member ring attached to the phenyl group.
Both the 2,3- and 3,4- indanyl (5 member alkyl ring) and the 2,3-
and 3,4- six member alkyl rings of the fused
cycloalkylphenyl-oxazolidin-2-ones (XXIA), are prepared by starting
with the appropriately substituted aniline (XVA). It is preferred
that n.sub.2 is 3 or 4.
The 2,3- and 3,4- fused alkanonephenyloxazolidin-2-ones (XXIB), are
prepared following the procedure for the preparation of the fused
cycloalkylphenyloxazolidin-2-ones (XXIA). The alkyl aniline
intermediate (XVA) is first oxidized to the corresponding alanone
aniline (XVB) by known procedures. See for example, J. Org. Chem.,
27, 70 (1962). The amino group is protected, for example as the
acetamide, and then the protected aniline (XVA) is oxidized to the
corresponding protected alkanone aniline (XVB) with an oxidizing
agent such as chromium trioxide in acetic acid and acetone. The
deprotected alanonephenyl aniline (XVB) is then reacted just as the
corresponding alkyl aniline (XVA) to produce the corresponding
alkanone (XXIB). It may be necessary to protect the ketone
functionality as the ketal with ethylene glycol, for example,
followed by deprotection with cid treatment at a later-stage. For
the 3,4-substitution, with a para ketone, with either the 5 or 6
member ring, alternatively and preferrably, the fused
cycloalkylphenyloxazolidin-2-one (XXIA) product can be oxidized
with an oxidizing agent such as chromium trioxide in acetic acid
and acetic anhydride directly to the corresponding fused
alkanonephenyloxazolidin-2 -one (XXIB) product. When the ketone
ring has a substituent on the carbon atom next to the carbonyl
group (either R.sub.10-1, R.sub.10-2, R.sub.10-3 or R.sub.10-4 is
not --H) the compounds are prepared by either starting with the
appropriately substituted aniline intermediate (XVB) or by
alkylation of the ketone (XXIB) or enamine (XXIH) at a later stage
in the synthesis as is known to those skilled in the art. When the
alkylation reaction is performed, it produces both the mono- and
dialkylated products. If the alkanonephenyloxazolidin-2-one (XXIB)
is alkylated; it is preferred that the
alkanonephenyloxazolidin-2-one (XXIB) be monoalkylated rather than
dialkylated. It is preferred that n.sub.3 +n.sub.4 +n.sub.7
+n.sub.2 =2 or 3. It is preferred that R.sub.10-3 is --CH.sub.3 or
--CH.sub.2 --OH and where R.sub.10-3 and R.sub.10-4 are taken
together to form cyclopropyl. It is more preferred that R.sub.10-1
is --CH.sub.3.
The fused hydroxycycloalkylphenyloxazolidin-2-ones (XXIC) are
prepared from the corresponding fused
alkanonephenyloxazolidin-2-ones (XXIB) by reduction with a reducing
agent such as sodium borohydride, sodium cyanoborohydride, lithium
borohydride, lithium trisec-butylborohydride, etc. The reduction of
the ketone to the corresponding secondary alcohol produces two
diastereomers which can be separated by chromatography or
crystallization. Both of the diastereomers have the desired
antibacterial activity, though in some cases to different degrees.
It is preferred that n.sub.3 +n.sub.4 =2 or 3. Treatment of the
alcohol with a base such as sodium hydride in the presence of an
alkylating agent such as an alkyl iodide or epoxide, results in the
formation of the corresponding either, --CH(--OR)--, as is known to
those skilled in the art. The fused
cycloalkenylphenyloxazolidin-2-ones (XXID) are preferrably produced
by the procedure of CHART D starting with the desired amino indene
or amino dihydronaphthalene (XVID). Alternatively, the indenes
(XXID) are produced by dehydration (alcohol elimination) of the
corresponding indanol (XXIC). Suitable reagents for the dehydration
include (CF.sub.3 --CO).sub.2 O, CH.sub.3 --SO.sub.2 --Cl or
(CF.sub.3 SO.sub.2).sub.2 O and triethylamine. Dehydration of a
benzylic substituted fused hydroxycycloalkylphenyloxazolidinone (C)
will result in the production of just one fused
cycloalkenylphenyloxazolidinone (D). However, with a non-benzylic
fused hydroxycycloalkylphenyloxazolidinone (C), two dehydration
products are produced. Both are within the scope of the invention.
It is preferred that n.sub.5 +n.sub.6 1 or 2.
The fused oximinocycloalkylphenyloxazolidin-2-ones (XXIE) are
prepared from the corresponding fused
alkanonephenyloxazolidin-2-ones (XXIB) by reaction with
hydroxylamine (R.sub.7 is --H) hydrochloride or a substituted
hydroxylamine (R.sub.7 is not --H) hydrochloride in the presence of
a base such as pyridine or sodium bicarbonate.
Once the aminomethyloxazolidin-2-ones (XX) are obtained various
analogues and/or derivatives can readily be prepared by acylation.
For pharmacological activity it is necessary that the 5-amidomethyl
side chain be in the .beta. configuration; hence, the --H at
C.sub.5 must be in the .alpha. configuration. It is preferred that
R.sub.1 be --CH.sub.3 and --OCH.sub.3, --CHCl.sub.2 and C.sub.3
-C.sub.6 cycloalkyl; it is more preferred that R.sub.1 be
--CH.sub.3.
The synthesis of the indazolyloxazolidin-2-ones (XXXII) starts with
the appropriate nitroindazole (XXII). It is preferred that R.sub.2,
R.sub.3 and R.sub.4 all be --H. It is preferred that R.sub.6 is --H
or --CH.sub.3. The indazolyl nitrogen of the nitroindazoles (XXII)
is protected, as previously discussed, to produce the corresponding
protected nitroindazoles (XXIII). It is preferred that X.sub.1 be
t-butyloxycarbonyl. Next, the nitro group of the protected
nitroindazoles (XXIII) is reduced with hydrogen, as previously
discussed, to the corresponding protected aminoindazoles (XXIV).
Acylation of free unprotected amino group of the protected
aminoindazoles (XXIV) with a carbobenzyloxy (CBZ) group gives the
urethanes (XXV). The urethanes (XXV) are then reacted with
Br--CH.sub.2 --CH.dbd.CH.sub.2 in THF and a base, as previously
discussed, forming the protected allyl compounds (XXVI) and the
bisallyl compounds (XXVI'). The protected allyl compounds (XXVI)
and the bisallyl compounds (XXVI') can be separated at this point
but it is preferrable to use the mixture as the starting material
for the next step. The protected allyl compounds (XXVI) and the
bisallyl compounds (XXVI') are cyclized to form the oxazolidinone
nucleus by reaction with an electrophilic agent, as previously
discussed. The oxazolidinone nuclei formed are the protected
iodomethyloxazolidin-2-ones (XXVIII) and the
allyliodomethyloxazolidin-2-ones (XXVII'). Following formation of
the oxazolidinone ring, the desired side chain at the 5-position is
formed, as previously discussed, to form the azides (XXVIII) and
allylazides (XXVIII'). During the reaction of the iodomethyl
compounds (XXVII/XXVII') to the corresponding azides
(XXVIII/XXVIII') the protecting group, X.sub.1, of the iodomethyl
compounds (VI) may be lost, see CHART E. In other cases it will be
retained and can be removed after the aminomethyl group is
acylated. The azides (XXVIII) and allylazides (XXVIII') can be
separated but it is preferred to not separate them at this stage
but to reduce the mixture. The azides (XXVIII) and allylazides
(XXVIII') are reduced with hydrogen, as previously discussed, to
give aminomethyloxazolidin-2-ones (XXIX) and
3-allyl-5-aminomethyloxazolidin-2-ones (XXIX'). When the
oxazolidinone nucleus is formed to give compounds (XXVII and
XXVII') an asymmetric center is created at C.sub.5 which give rise
to a racemic mixture. It is preferrable to resolve the racemic
mixture, if desired, at the aminomethyloxazolidin-2-one (XXIX) and
allylaminomethyloxazolidin-2-one (XXIX') stage using methods known
to those skilled in the art, as previously discussed.
The aminomethyloxazolidin-2-ones (XXIX) and
allylaminomethyloxazolidin-2-ones (XXIX') are then acylated to
produce the protected indazolyloxazolidin-2-ones (XXX), unprotected
indazolyloxazolidin-2-ones (XXXI) and allyl
indazolyloxazolidin-2-ones (XXX') containing the desired R.sub.1
group at C.sub.5. In the case of the indazolyloxazolidin-2-ones
(XXX) the acylation produces the bis acylated compound with the
acyl group also at the 1-indazolyl position. In most cases this
will be a desired product and therefore is in the scope of the
claimed indazolyloxazolidin-2-ones (XXXII). The allyl
indazolyloxazolidin-2-ones (XXXII') are useful pharmacological
agents and intermediates within the scope of the
indazolyloxazolidin-2-ones (XXXII). It is preferred that R.sub.1 is
H, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, --OCH.sub.3
and --CHCl.sub.2 ; it is more preferred that R.sub.1 is
--CH.sub.3.
In the cases where the protecting group, X.sub.1, was not cleaved
by azide the protecting group is then removed, for example, by
trifluoroacetic acid treatment to give the unprotected
indazolyloxazolidin-2-ones (XXXI).
The unprotected indazolyloxazolidin-2-ones (XXXI) are then
N-acylated or N-alkylated, if necessary, with the desired R.sub.5
group, either as the acid halide, anhydride, or alkyl halide to
produce the desired indazolyloxazolidin-2-ones (XXXII). For the
indazolyloxazolidin-2-ones (XXXII), it is preferred that R.sub.5 is
selected from the group consisting of --CH.sub.3, --CH.sub.2
--C.tbd.CH, --CHO, --CO--R.sub.5-1 where R.sub.5-1 is --CH.sub.3,
--C.sub.2 H.sub.5, --CH(CH.sub.3).sub.2, --CHCl.sub.2, --CH.sub.2
--O--CH.sub.3 and cyclopentyl. It is more preferred that R.sub.5 is
--CH.sub.3, --CHO, --CO--R.sub.5-1 where R.sub.5-1 is --CH.sub.3,
--C.sub.2 H.sub.5, --CHCl.sub.2, --CH.sub.2 --O--CH.sub.3.
The benzimidazolyloxazolidin-2-ones (XLIII) and the
benzotriazolyloxazolidin-2-ones (LIV) are prepared in a similar
manner (compare CHARTS F and G) to the indazolyloxazolidin-2-ones
(XXXII) (CHART E) with the following exceptions. First, with the
indazolyl compounds when transforming the urethane (XXV) to the
protected allyl compound (XXVI), the allyl group replaced the
protecting group (X.sub.1) to some extent producing the
bisallylindazolyl compounds (XXVI'); with the
benzimidazolyloxazolidin-2-ones (XLIII) and the
benzotriazolyloxazolidin-2-ones (LIV) the X.sub.1 protecting group
is not lost when transforming the urethanes (XXXVI and XLVII) to
the protected compounds (XXXVII and XLVIII) respectively. Second,
with the indazolyl compounds when reducing the azide (XXVIII) with
hydrogen again the protecting group is lost producing the
aminomethyl compounds (XXIX); with the
benzimidazolyloxazolidin-2-ones (XLIII) and the
benzotriazolyloxazolidin-2-ones (LIV) the protecting group X.sub.1
is not lost when reducing the protected azides (XXXIX and L)
respectively.
In producing the benzimidazolyloxazolidin-2-ones (XLIII), in many
cases the desired R.sub.5 group of the
benzimidazolyloxazolidin-2-ones (XLIII) may be the same as the
protecting group X.sub.1 in the intermediate precursors
(XXXIV-XLI). In those cases the protected
benzimidazolyloxazolidin-2-ones (XLI) are identical to the
benzimidazolyloxazolidin-2-ones (XLIII), and therefore one has
obtained the useful end product when obtaining the protected
benzimidazolyloxazolidinones (XLI).
For the benzimidazolyloxazolidin-2-ones (XLIII) it is preferred
that R.sub.6 is --H or C.sub.1 -C.sub.6 alkyl.
The 5'-indolinyloxazolidin-2-ones (XI), the 3-(fused-ring
substituted)phenyl-5.beta.-amidomethyloxazolidin-2-ones (XXI), the
indazolyloxazolidin-2-ones (XXXII), the
benzimidazolyloxazolidin-2-ones (XLIII) and the
benzotriazolyloxazolidin-2-ones (XLIV) all have an asymmetric
center at the C.sub.5 -position of the oxazolidinone ring which
produces two enantiomers. The mixture of enantiomers is resolved by
means known to those skilled in the art. The enantiomer which is
pharmacologically active is the .beta.-enantiomer, see CHARTS A
thru G. The racemic mixture is useful in the same way and for the
same purpose as the pure .beta.-enantiomer; the difference is that
twice as much racemic material must be used to produce the same
effect as the pure .beta.-enantiomer.
For the convenience the indazolyloxazolidin-2-ones (XXXII),
benzimidazolyloxazolidin-2-ones (XLIII) and
benzotriazolyloxazolidin-2-ones (LIV) will be collectively referred
to as the 3-(nitrogen
substituted)phenyl-5.beta.-amidomethyloxazolidin-2-ones (LV).
The 5'-indolinyloxazolidin-2-ones (XI), 3-(fused-ring
substituted)phenyl-5.beta.-(amidomethyl)oxazolidin-2-ones (XXI) and
the 3-(nitrogen
substituted)phenyl-5.beta.-(amidomethyl)oxazolidin-2-ones (LV) of
the present invention are useful as antibacterial agents in
treating infections in mammals caused by gram-positive and
anaerobic infections. It is preferred to treat humans and useful
warm-blooded mammals such as cattle, horses, sheep, hogs, dogs,
cats, etc.
The 5'-indolinyloxazolidin-2-ones (XI), 3-(fused-ring
substituted)phenyl-5.beta.-(amidomethyl oxazolidin-2-ones (XXI) and
the 3-(nitrogen
substituted)phenyl-5.beta.-(amidomethyl)oxazolidin-2-ones (LV) of
the present invention are also useful in treating AIDS patients
infected with Mycobacterium avium.
The 5'-indolinyloxazolidin-2-ones (XI), 3-(fused-ring
substituted)phenyl-5.beta.-(amidomethyl) oxazolidin-2-ones (XXI)
and the 3-(nitrogen
substituted)phenyl-5.beta.-(amidomethyl)oxazolidin-2-ones (LV) can
be administered either parenterally (IV, IM, SQ) or orally. The
daily dose is about 5 to about 20 mg/kg. This dose can preferrably
be given in divided doses and administered 2-4 times daily. The
preferred route of administration as well as the particular dosage
form for either the parenteral or oral route depends on the
particular facts of the situation including the nature of the
infection and condition of the patient. The usual pharmaceutical
dosage forms appropriate for parenteral (solution, suspension in
oil) and oral (tablet, capsule, syrup, suspension, etc.)
administration are known to those skilled in the art and there is
nothing unusual about using those dosage forms with the
5'-indolinyloxazolidin-2-ones (XI), the 3-(fused-ring
substituted)phenyl-5.beta.-(amidomethyl)oxazolidin-2-ones (XXI) and
the 3-(nitrogen
substituted)phenyl-5.beta.-(amidomethyl)oxazolidin-2-ones (LV). The
exact dosage of the 5'-indolinyloxazolidin-2-ones (XI), the
3-(fused-ring
substituted)phenyl-5.beta.-(amidomethyl)oxazolidin-2-ones (XXI) and
the 3-(nitrogen
substituted)phenyl-5.beta.-(amidomethyl)oxazolidin-2-ones (LV) to
be administered, the frequency of administration, route of
administration, the dosage form will vary depending on a number of
factors known to those skilled in the art including the age,
weight, sex, general physical condition of the patient, the nature
of the infection (particular microorganism involved, its virulence,
the extent of the infection) other medical problems of the patient,
etc. as is well known to the physical treating infectious
diseases.
The 5'-indolinyloxazolidin-2-ones (XI), the 3-(fused-ring
substituted)phenyl-5.beta.-(amidomethyl) oxazolidin-2-ones (XXI)
and the 3-(nitrogen
substituted)phenyl-5.beta.-(amidomethyl)oxazolidin-2-ones (LV) can
be used either alone or in conjunction with other antibacterial
agents as is known to those skilled in the art. Further, the
5'-indolinyloxazolidin-2-ones (XI), the 3-(fused-ring
substituted)phenyl-5.beta.-(amidomethyl)oxazolidin-2-ones (XXI) and
the 3-(nitrogen
substituted)phenyl-5.beta.-(amidomethyl)oxazolidin-2-ones (LV) can
be used in conjunction with non-antibacterial agents as is known to
those skilled in the art.
Suitable pharmaceutically acceptable salts include, for example,
chloride, sulfate, phosphate, citrate and oxylate.
DEFINITIONS AND CONVENTIONS
The definitions and explanations below are for the terms as used
throughout this entire document including both the specification
and the claims.
I. CONVENTIONS FOR FORMULAS AND DEFINITIONS OF VARIABLES
The chemical formulas representing various compounds or molecular
fragments in the specification and claims may contain variable
substituents in addition to expressly defined structural features.
These variable substituents are identified by a letter or a letter
followed by a numerical subscript, for example, "Z.sub.1 " or
"R.sub.i " where "i" is an integer. These variable substituents are
either monovalent or bivalent, that is, they represent a group
attached to the formula by one or two chemical bonds. For example,
a group Z.sub.1 would represent a bivalent variable if attached to
the formula CH.sub.3 --C(.dbd.Z.sub.1)H. Groups R.sub.i and R.sub.j
would represent monovalent variable substituents if attached to the
formula CH.sub.3 --CH.sub.2 --C(R.sub.i)(R.sub.j)H.sub.2. When
chemical formulas are drawn in a linear fashion, such as those
above, variable substituents contained in parentheses are bonded to
the atom immediately to the left of the variable substituent
enclosed in parenthesis. When two or more consecutive variable
substituents are enclosed in parentheses, each of the consecutive
variable substituents is bonded to the immediately preceding atom
to the left which is not enclosed in parentheses. Thus, in the
formula above, both R.sub.i and R.sub.j are bonded to the preceding
carbon atom.
Chemical formulas or portions thereof drawn in a linear fashion
represent atoms in a linear chain. The symbol "-" in general
represents a bond between two atoms in the chain. Thus CH.sub.3
--O--CH.sub.2 --CH(R.sub.i)--CH.sub.3 represents a
2-substituted-1-methoxypropane compound. In a similar fashion, the
symbol ".dbd." represent a double bond, e.g., CH.sub.2
.dbd.C(R.sub.i)--O--CH.sub.3, and the symbol ".tbd." represents a
triple bond, e.g., HC.tbd.C--CH(R.sub.i)--CH.sub.2 --CH.sub.3.
Carbonyl groups are represented in either one of two ways: --CO--
or --C(.dbd.O)--, with the former being preferred for
simplicity.
Chemical formulas of cyclic (ring) compounds or molecular fragments
can be represented in a linear fashion. Thus, the compound
4-chloro-2-methylpyridine can be represented in linear fashion by
N*.dbd.C(CH.sub.3)--CH.dbd.CCl--CH.dbd.C*H with the convention that
the atoms marked with an asterisk (*) are bonded to each other
resulting in the formation of a ring. Likewise, the cyclic
molecular fragment, 4-(ethyl)-1-piperazinyl can be represented by
--N*--(CH.sub.2).sub.2 --N(C.sub.2 H.sub.5)--CH.sub.2
--C*H.sub.2.
A rigid cyclic (ring) structure for any compounds herein defines an
orientation with respect to the plane of the ring for substituents
attached to each carbon atom of the rigid cyclic compound. For
saturated compounds which have two substituents attached to a
carbon atom which is part of a cyclic system,
--C(X.sub.1)(X.sub.2)-- the two substituents may be in either an
axial or equatorial position relative to the ring and may change
between axial/equatorial. However, the position of the two
substituents relative to the ring and each other remains fixed.
While either substituent at times may lie in the plane of the ring
(equatorial) rather than above or below the plane (axial), one
substituent is always above the other. In formulas depicting such
compounds, a substituent (X.sub.1) which is "bellow" another
substituent (X.sub.2) will be identified as being in the alpha
(.alpha.) configuration and is identified by a broken, dashed or
dotted line attachment to the carbon atom, i.e., by the symbol
"---" or "...". The corresponding substituent attached "above"
(X.sub.2) the other (X.sub.1) is identified as being in the beta
(.beta.) configuration and is indicated by an unbroken line
attachment to the carbon atom.
When a variable substituent is bivalent, the valences may be taken
together or separately or both in the definition of the variable.
For example, a variable R.sub.i attached to a carbon atom as
--C(.dbd.R.sub.i)-- might be bivalent and be defined as oxo or keto
(thus forming a carbonyl group (--CO--) or as two separately
attached monovalent variable substituents .alpha.--R.sub.i-j and
.beta.--R.sub.i-k. When a bivalent variable, R.sub.i, is defined to
consist of two monovalent variable substituents, the convention
used to define the bivalent variable is of the form
".alpha.--R.sub.i-j :.beta.--R.sub.i-k " or some variant thereof.
In such a case both .alpha.--R.sub.i-j and .beta.--R.sub.i-k are
attached to the carbon atom to give
--C(.alpha.--R.sub.ij)(.beta.--R.sub.i-k)--. For example, when the
bivalent variable R.sub.6, 'C(.dbd.R.sub.6)-- is defined to consist
of two monovalent variable substituents, two monovalent variable
substituents are .alpha.--R.sub.6-1 :.beta.--R.sub.6-2, . . .
.alpha.--R.sub.6-9 :.beta.--R.sub.6-10, etc., giving
--C(.alpha.--R.sub. 6-1)(.beta.--R.sub.6-2)--, . . .
--C(.alpha.--R.sub.6-9) (.beta.--R.sub.6-10)--, etc. Likewise, for
the bivalent variable R.sub.11, --C(.dbd.R.sub.11)--, two
monovalent variable substituents are .alpha.--R.sub.11-1
:.beta.--R.sub.11-2. For a ring substituent for which separate
.alpha. and .beta. orientations do not exist (e.g. due to the
presence of a carbon carbon double bond in the ring), and for a
substituent bonded to a carbon atom which is not part of a ring the
above convention is still used, but the .alpha. and .beta.
designations are omitted.
Just as a bivalent variable may be defined as two separate
monovalent variable substituents, two separate monovalent variable
substituents may be defined to be taken together to form a bivalent
variable. For example, in the formula --C.sub.1 (R.sub.i)H--C.sub.2
(R.sub.j)H-- (C.sub.1 and C.sub.2 define arbitrarily a first and
second carbon atom, respectively) R.sub.i and R.sub.j may be
defined to be taken together to form (1) a second bond between
C.sub.1 and C.sub.2 or (2) a bivalent group such as oxa (--O--) and
the formula thereby described an epoxide. When R.sub.i and R.sub.j
are taken together to form a more complex entity, such as the group
--X--Y--, then the orientation of the entity is such that Cj.sub.1
in the above formula is bonded to X and C.sub.2 is bonded to Y.
Thus, by convention the designation "...R.sub.i and R.sub.j are
taken together to form --CH.sub.2 --CH.sub.2 --O--CO--..." means a
lactone in which the carbonyl is bonded to C.sub.2. However, when
designated "... R.sub.j and R.sub.i are taken together to form
--CH.sub.2 --CH.sub.2 --O--CO-- the convention means a lactone in
which the carbonyl is bonded to C.sub.1.
The carbon atom content of variable substituents is indicated in
one of two ways. The first method uses a prefix to the entire name
of the variable such as "C.sub.1 -C.sub.4 ", where both "1" and "4"
are integers representing the minimum and maximum number of carbon
atoms in the variable. The prefix is separated from the variable by
a space. For example, "C.sub.1 -C.sub.4 alkyl" represents alkyl of
1 through 4 carbon atoms, (including isomeric forms thereof unless
an express indication to the contrary is given). Whenever this
single prefix is given, the prefix indicates the entire carbon atom
content of the variable being defined. Thus C.sub.2 -C.sub.4
alkoxycarbonyl describes a group CH.sub.3 --(CH.sub.2).sub.n
--O--CO-- where n is zero one or 2. By the second method the carbon
atom content of only each portion of the definition is indicated
separately by enclosing the "C.sub.i -C.sub.j " designation in
parentheses and placing it immediately (no intervening space)
before the portion of the definition being defined. By this
optional convention (C.sub.1 -C.sub.3)alkoxycarbonyl has the same
meaning as C.sub.2 -C.sub.4 alkoxycarbonyl because the "C.sub.1
-C.sub.3 " refers only to the carbon atom content of the alkoxy
group. Similarly while both C.sub.2 -C.sub.6 alkoxyalkyl and
(C.sub.1 -C.sub.3)alkoxy(C.sub.1 -C.sub.3)alkyl define alkoxyalkyl
groups containing from 2 to 6 carbon atoms, the two definitions
differ since the former definition allows either the alkoxy or
alkyl portion alone to contain 4 or 5 carbon atoms while the latter
definition limits either of these groups to 3 carbon atoms.
II. DEFINITIONS
All temperatures are in degrees Centigrade.
TLC refers to thin-layer chromatography.
THF refers to tetrahydrofuran.
THP refers to tetrohydropyanyl.
DMF refers to dimethylformamide.
TEA refers to triethylamine.
Alcohol refers to ethyl alcohol.
MPLC refers to medium pressure liquid chromatography.
Saline refers to an aqueous saturated sodium chloride solution.
IR refers to infrared spectroscopy.
CMR refers to C-13 magnetic resonance spectroscopy, chemical shifts
are reported in ppm (.delta.) downfield from TMS.
NMR refers to nuclear (proton) magnetic resonance spectroscopy,
chemical shifts are reported in ppm (.delta.) downfield from
tetramethylsilane.
TMS refers to trimethylsilyl.
.phi. refers to phenyl (C.sub.6 H.sub.5).
MS refers to mass spectrometry expressed as m/e or mass/charge
unit. [M+H].sup.+ refers to the positive ion of a parent plus a
hydrogen atom. EI refers to electron impact. CI refers to chemical
ionization. FAB refers to fast atom bombardment.
Pharmaceutically acceptable refers to those properties and/or
substances which are acceptable to the patient from a
pharmacological/toxicological point of view and to the
manufacturing pharmaceutical chemist from a physical/chemical point
of view regarding composition, formulation, stability, patient
acceptance and bioavailability.
When solvent pairs are used, the ratios of solvents used are
volume/volume (v/v).
.sub.-- indicates that there are 2 possible orientations for the
attached group, (1) .alpha. or .beta. when attached to the ring and
(2) cis or trans when attached to a carbon atom of a double
bond.
BOC refers to t-butyloxycarbonyl, --CO--O--C(CH.sub.3).sub.3.
CBZ refers to carbobenzyloxy, --CO--O--CH.sub.2 --.phi..
EXAMPLES
Without further elaboration, it is believed that one skilled in the
art can, using the preceding description, practice the present
invention to its fullest extent. The following detailed examples
describe how to prepare the various compounds and/or perform the
various processes of the invention and are to be construed as
merely illustrative, and not limitations of the preceding
disclosure in any way whatsoever. Those skilled in the art will
promptly recognize appropriate variations from the procedures both
as to reactants and as to reaction conditions and techniques.
EXAMPLE 1
N-Acetyl-5-nitroindoline (II)
A mixture of 5-nitroindoline (I, 12.012 g) in pyridine (100 ml) and
acetic anhydride (50 ml) is stirred for 17 hr under argon. The
mixture is then concentrated under reduced pressure to give the
title compound, mp 175.degree.-177.degree.; NMR (CDCl.sub.3, 300
MHz) 8.28, 8.10, 8.01, 4.23, 3.31 and 2.28 .delta.; CMR
(CDCl.sub.3, 75.47 MHz) 23.95, 27.01, 49.11, 115.73, 119.93,
124.27, 132.4, 143.4 and 169.8 .delta.; IR (CHCl.sub.3) 1680, 1600,
1480, 1470, 1390, 1340 and 1320 cm.sup.-1.
EXAMPLE 2
N-Acetyl-5-aminoindoline (III)
Palladium on carbon (10%, 1.110 g) is added to a mixture of
N-acetyl-5-nitro indoline (II, EXAMPLE 1, 5.00 g) in ethyl acetate
(freshly opened bottle, about 500 ml). The mixture is stirred under
1 atm of hydrogen (balloon) for 39 hr then filtered and the
palladium on carbon is washed with methanol/ethyl acetate (20/80).
The filtrate is concentrated under reduced pressure to give the
title compound, mp 183.degree.-185.degree.; NMR (CDCl.sub.3, 300
MHz) 8.01, 6.53, 6.50, 3.98, 3.56, 3.04 and 2.17 .delta.; CMR
(CDCl.sub.3, 75.47 MHz) 23.86, 28.05, 48.71, 111.55, 113.73,
117.66, 132.8, 135.6, 149.1 and 168.1 .delta.; IR (CHCl.sub.3)
3000, 1640, 1600, 1490, 1410, 1330 and 1300 cm.sup.-1.
EXAMPLE 3
1-Acetyl-(N-carbobenzyloxy)-5-aminoindoline (IV)
Benzyl chloroformate (1.2 ml) is added to a solution of
N-acetyl-5-aminoindoline (III, EXAMPLE 2, 1.4 g) and sodium
bicarbonate (1.33 g) in acetone/water (40/60, 20 ml) at 0.degree..
The mixture is stirred for 2.5 hr, then benzyl chloroformate 90.5
ml) is added. After stirring for 2.3 hr, the mixture is poured into
chloroform (25 ml) and the organic layers are washed with aqueous
sodium bisulfate (10%, 2.times.) and then washed with aqueous
sodium carbonate (10%, 2.times.). Chloroform (about 200 ml) is
added to the aqueous layers and then the organic layers are washed
again with aqueous sodium bisulfate (10%), aqueous sodium carbonate
(10%), then dried over magnesium sulfate, and concentrated under
reduced pressure to give the title compound,
180.degree.-182.degree.; NMR (CDCl.sub.3, 300 MHz) 8.03, 7.38,
7.30-7.23, 6.98, 6.90, 5.09, 3.90, 3.05 and 2.09 .delta.; CMR
(CDCl.sub.3, 75.47 MHz) 23.98, 28.07, 48.90, 66.89, 115.9, 117.05,
118.1, 128.25, 128.59, 132.22, 133.78, 136.21, 139.4, 154.2 and
168.39 .delta.; IR (CHCl.sub.3) 3440, 1730, 1660, 1600, 1490 and
1400 cm.sup.-1.
EXAMPLE 4
1-Acetyl-(N-allyl-N-carbobenzyloxy)-5-aminoindoline (V)
Sodium hydride/mineral oil (50% w/w, 425 mg) is added to a mixture
of 1-acetyl-(N-carbobenzyloxy)-5-aminoindoline (IV, EXAMPLE 3, 2.00
g) in THF (freshly distilled 80 ml). Allyl bromide (0.725 ml) is
added and the mixture is refluxed for 26.5 hr under nitrogen. At
the end of this time it is poured into water and extracted with
ethyl acetate (3.times.). The organic layers are combined and dried
over magnesium sulfate and concentrated under reduced pressure to a
solid which is purified on a 40-63.mu. silica column eluting with a
gradient from 100% hexane to 100% ethyl acetate. The appropriate
fractions are pooled and concentrated to give the title compound,
mp 108.degree.-100.degree.; NMR (CDCl.sub.3, 300 MHZ) 8.17, 7.29,
7.03, 5.9, 5.14, 5.1, 4.24, 4.00, 3.13 and 2.17 .delta.; CMR
(CDCl.sub.3, 75.47 MHz) 23.80, 27.54, 48.69, 53.23, 66.98, 116.57,
117.01, 123.13, 126.2, 127.38, 127.60, 128.13, 131.61, 133.37,
136.35, 137.3, 141.6, 155.12 and 168.33; IR (CHCl.sub. 3) 1700,
1650, 1490 and 1400 cm.sup.-1 ; MS (m/e) 350, 215, 173 and 91;
exact mass calc'd for C.sub.21 H.sub.22 N.sub.2 O.sub.3 =350.1630,
found 350.1607.
EXAMPLE 5
(.+-.)-3-(5'-1-Acetylindolinyl)-5-(iodomethyl)oxazolidin-2-one
(VI)
Iodine (1.94 g) is added to a mixture of
1-acetyl-(N-allyl-N-carbobenzyloxy)-5-aminoindoline (V, EXAMPLE 4,
1.3 g) in chloroform (20 ml). After stirring for 3 hr under
nitrogen the mixture is poured into additional chloroform and
washed with aqueous sodium thiosulfate (10%, 2.times.), dried over
sodium sulfate and concentrated under reduced pressure to give the
title compound, mp 188.degree.-190.degree.; NMR (CDCl.sub.3, 300
MHz) 8.17, 7.66, 7.01, 4.7, 4.15, 4.06, 3.76, 3.46, 3.36 and 2.22
.delta.; CMR (CDCl.sub.3, 75.47 MHz) 6.13, 23.98, 28.00, 48.82,
51.30, 71.09, 115.621, 116.73, 117.00, 132.38, 133.7, 139.9, 154.4
and 168.44 .delta.; IR (CHCl.sub.3) 1760, 1660, 1490 and 1400
cm.sup.-1 ; MS (m/e) 386, 344, 299, 258, 216, 189, 173, 158, 145,
132; exact mass calcd for C.sub.14 H.sub.15 IN.sub.2 O.sub.3
=386.0129, found 386.0130.
EXAMPLE 6
(+)-3-(5'-1-Acetylindolinyl)-5-(azidomethyl)oxazolidin-2-one
(VII)
Sodium azide (1.005 g) in water (10 ml) is added to a mixture of
(.+-.)-3-(5'-1-acetylindolinyl)-5-(iodomethyl)oxazolidin-2-one (VI,
EXAMPLE 5, 0.798 g) in acetone (150 ml). The mixture is refluxed
under nitrogen for 42.5 hr then poured into water 9225 ml). The
aqueous layer is extracted with ethyl acetate (3.times., 400 ml).
The combined organic layers are washed with water (500 ml), with
saline (300 ml) then dried over magnesium sulfate and concentrated
under reduced pressure to give the title compound, mp
165.degree.-166.degree.; NMR (CDCl.sub.3, 300 MHz) 8.08, 7.57, 6.9,
4.7, 4.0, 3.75, 3.62, 3.5, 3.11 and 2.14 .delta.; CMR (CDCl.sub.3,
75.47 MHz) 23.92, 27.94, 47.69, 48.78, 52.97, 70.52, 115.48,
116.62, 116.82, 132.37, 133.48, 139.45, 153.97 and 168.43.delta.;
IR (CHCl.sub.3) 2105, 1750, 1650, 1480 and 1390 cm.sup.-1 ; MS
(m/e) 301, 273, 229, 160, 146, 132 and 117 ; exact mass calcd for
C.sub.14 H.sub.15 N.sub.5 O.sub.3 =301.1174, found 301.1194.
EXAMPLE 7
(.+-.)-3-(5'-1-Acetylindolinyl)-5-(aminomethyl)oxazolidin-2-one
(VIII)
Palladium on carbon (10%, 110 mg) is added to a mixture of
(+)-3-(5'-1-acetylindolinyl) -5-(azidomethyl)oxazolidin-2-one (VII,
EXAMPLE 6, 550 mg) in methanol/ethyl acetate (8/92, 130 ml). The
mixture is stirred for 24 hr under 1 atm (balloon) of hydrogen. The
solution is filtered and the filtrate is concentrated under reduced
pressure to give the title compound, 164.degree.-165.degree.; NMR
(CDCl.sub.3, 300 MHz) 8.08, 7.61, 6.9, 4.58, 3.98, 3.75, 3.11,
3.02, 2.90, 2.14 and 1.33; CMR (CDCl.sub.3, 300 MHz) 8.08, 7.61,
6.9, 4.58, 3.98, 3.75, 3.11, 3.02, 2.90, 2.14 and 1.33; CMR
(CDCl.sub.3, 75.47 MHz) 23.96, 28.00, 44.96, 47.93, 48.82, 73.79,
115.40, 115.67, 132.29, 133.97, 139.6, 155.2 and 168.40 .delta.; IR
(CHCl.sub.3) 1750, 1650, 1490, 1400 and 900 cm.sup.-1 ; MS (m/e)
275, 233, 189, 160, 147 and 117.
EXAMPLE 8
(.+-.)-3-(5'-1-Acetylindolinyl)-5-(acetamidomethyl)oxazolidin-2-one
(IX)
A mixture of
(.+-.)-3-(5'-1-acetylindolinyl)-5-(aminomethyl)oxazolidin-2-one
(VIII, EXAMPLE 7, 200 mg) in pyridine (5 ml) and acetic anhydride
(2.5 ml) is stirred overnight. The mixture then is concentrated
under reduced pressure to give a solid. The solid is recrystallized
by dissolving in as little chloroform and methanol as possible then
added to an equal volume of ethyl acetate and concentrated by
evaporation under a nitrogen stream to give the title compound, mp
234.degree.-235.degree.; NMR (CDCl.sub.3, 300 MHz) 8.16, 7.58,
7.03, 6.37, 4.76, 4.04, 3.76, 3.65, 3.20, 2.23 and 2.03 .delta.l
CMR (CDCl.sub.3, 75.47 MHz) 23.00, 23.95, 27.99, 30.81, 41.90,
47.88, 48.81, 71.70, 115.44, 116.82, 117.13, 132.27, 133.55,
139.53, 154.45, 168.46 and 170.92 .delta.; IR (CHCl.sub.3) 1755,
1670, 1490 and 1400 cm.sup.-1 ; MS (m/e) 317, 273, 189, 172, 159,
147 and 117.
EXAMPLE 9
1-Carbo-t-butyloxy-5-nitroindoline (II)
Di-tert-butyldicarbonate (13.4 g) is added all at once to a
solution of 5-nitroindoline (I, 5.00 g) in freshly distilled THF
(85 ml). The mixture is refluxed for three days then
di-tert-butyldicarbonate (9.90 g) is added and the mixture refluxed
overnight. The mixture is poured into water (225 ml), this is
extracted with ethyl acetate (4.times., total 450 ml). The combined
organic layers are washed with aqueous sodium bicarbonate (5%, 500
ml), saline, dried over magnesium sulfate and concentrated under
reduced pressure. The mixture of solid and oil is triturated in
hexane and filtered to give the title compound, NMR (CDCl.sub.3,
300 MHz) 8.10, 7.99, 7.85, 4.09, 3.17 and 1.58 .delta.; CMR
(CDCl.sub.3, 75.47 MHz) 26.38, 28.11, 48.32, 81.8, 113.58, 120.28,
124.53, 142.38 and 151.82; IR (CHCl.sub.3) 1710, 1605, 1490, 1395
and 1320 cm.sup.-1 ; MS (m/e) 264,208, 164 and 57; exact mass calcd
for C.sub.13 H.sub.16 N.sub.2 O.sub. 4 =264.1110, found
264.1117.
EXAMPLE 10
1-Carbo-t-butyloxy-5-aminoindoline (III)
Palladium on carbon (10%, 1.0 g) is added to a mixture of
1-carbo-t-butyloxy-5-nitroindoline (II, EXAMPLE 9, 4.554 g) in
ethyl acetate (freshly opened bottle, 500 ml) at 0.degree.. The
mixture is stirred under 1 atm of hydrogen (balloon ) at
20.degree.-25.degree. for 3.5 hr. The mixture is then filtered and
concentrated under reduced pressure. The concentrated filtrate is
taken up in ethyl acetate and washed with saline (3.times.). The
combined aqueous layers are extracted with ethyl acetate
(3.times.). All organic phases are combined and washed with saline,
dried over magnesium sulfate and concentrated under reduced
pressure to give the title compound, NMR (CDCl.sub.3, 300 MHz)
7.64, 7.26, 6.50, 3.93, 3.48, 3.00 and 1.54 .delta.; CMR
(CDCl.sub.3, 75.47 MHz) 27.47, 28.42, 47.41, 77.39, 79.6, 80.6,
112.14, 113.67, 115.15, 132.4, 133.0, 134.5, 135.2, 141.71 and
152.36; IR (CHCl.sub.3) 3360, 3440, 1680, 1485 and 1390 cm.sup.-1 ;
MS (m/e) 234, 178, 134 and 57.
EXAMPLE 11
1-Carbo-t-butyloxy-(N-carbobenzyloxy)-5-aminoindoline (IV)
Benzyl chloroformate (2.1 ml) is added to a mixture of
1-carbo-t-butyloxy-5-aminoindoline (III, EXAMPLE 10, 3.147 g) and
sodium bicarbonate (2.40 g) in acetone/water (55/45, 40 ml) at
0.degree.. After stirring for one hour, chloroform (50 ml) is added
to the mixture. The mixture is then poured into ethyl acetate (50
ml) and washed with saline. The aqueous layer is then extracted
with ethyl acetate (2.times. for total of 200 ml). The organic
layers combined and washed with aqueous sodium bisulfate 910%,
2.times.100 ml), aqueous sodium carbonate 910%, 2.times.100 ml),
saline (100 ml), dried over magnesium sulfate then concentrated
under reduced pressure to give the title compound, NMR (CDCl.sub.3,
300 MHz) 7.74, 7.33, 7.00, 5.14, 3.92, 2.98, and 1.54 .delta.; CMR
(CDCl.sub.3, 300 MHz) 27.0, 28.303, 46.1, 47.52, 66.66, 73.3, 80.1,
81.0, 114.51, 118.00, 128.05, 128.38, 132.2, 132.36, 136.09, 138.3,
138.9, 152.37 and 153.60 .delta.; IR (CHCl.sub.3 ) 3430, 1730,
1685, 1485, 1385 cm.sup.-1.
EXAMPLE 12
1-Carbo-t-butyloxy-(N-allyl-N-carbobenzyloxy)-5-aminoindoline
(V)
Sodium hydride/mineral oil (50% w/w, 800 mg) is added to a mixture
of 1-carbo-t-butyloxy-(N-carbobenzyloxy) -5-aminoindoline (IV,
EXAMPLE 11, 4.480 g) in freshly distilled THF (180 ml). Allyl
bromide (1.32 ml) is added and the mixture is refluxed for 5.5 hr
under nitrogen, then it is poured into water and extracted with
ethyl acetate (3.times.). The combined organic layers are washed
with saline and dried over magnesium sulfate and then concentrated
under reduced pressure to an oil which is passed over a silica
column (40-63.mu.) eluting with a hexane - ethyl acetate gradient
(100% to 100%). The appropriate fractions are poled to give the
title compound, NMR (CDCl.sub.3, 300 MHz) 7.80, 7.29, 6.98, 5.87,
5.14, 5.10, 4.23, 3.96, 3.04 and 1.55 .delta.; CMR (CDCl.sub.3,
75.47 MHz) 27.11, 28.41, 47.80, 53.54, 67.16, 77.35, 80.5, 114.55,
117.23, 126.5, 127.60, 127.80, 128.35, 132.0, 133.69, 136.4,
136.72, 141.6, 152.43 and 155.47 .delta.; IR (CHCl.sub.3) 1690,
1490, 1395 and 1160 cm.sup.-1.
EXAMPLE 13
(.+-.)-3-(5'-1-Carbo-t-butyloxyindolinyl)-5-(iodomethyl)oxazolidin-2-one
(VI)
Iodine (5.512 g) is added to a mixture of
1-carbo-t-butyloxy-(N-allyl-N-carbobenzyloxy) -5-aminoindoline (V,
EXAMPLE 12, 4.190 g) in chloroform (65 ml). After stirring for 3 hr
the mixture is poured into chloroform (40 ml), washed with aqueous
sodium thiosulfate (10%, 3.times.100 ml), dried over magnesium
sulfate and concentrated under reduced pressure to a residue. The
residue is passed over a silica column (40-63.mu.) eluting with
ethyl acetate/hexane (10/90) then eluted with chloroform. The
appropriate fractions are poled and concentrated to a solid which
is recrystallized from acetone/water to give the title compound, mp
174.degree.-175.degree.; NMR (CDCl.sub.3, 300 MHz) 7.80, 7.53,
7.07, 4.69, 4.13, 3.98, 3.74, 3.45, 3.35, 3.09 and 1.56 .delta.;
CMR (CDCl.sub.3, 75.47 MHz) 6.18, 27.0, 28.26, 47.54, 51.34, 70.94,
80.6, 114.35, 115.96, 117.36, 132.17, 139.8, 152.24 and 154.01
.delta.; IR (CHCl.sub.3) 1760, 1690, 1490, 1390, 1370, 1145,
cm.sup.-1.
EXAMPLE 14
(.+-.)-3-(5'-1-Carbo-t-butyloxyindolinyl)-5-(azidomethyl)oxazolidin-2-one
(VII)
Following the general procedure of EXAMPLE 6 and making
non-critical variations but starting with
(.+-.)-3-(5'-1-carbo-t-butyloxyindolinyl)-5-(iodomethyl)oxazolidin-2-one
(VI, EXAMPLE 13), the title compound is obtained, mp
168.degree.-170.degree..
EXAMPLE 15
(.+-.)-3-(5'-1-Carbo-t-butyloxyindolinyl)-5-(aminomethyl)oxazolidin-2-one
(VIII)
Following the general procedure of EXAMPLE 7 and making
non-critical variations but starting with
(.+-.)-3-(5'-1-carbo-t-butyloxyindolinyl)-5-(azidomethyl)oxazolidin-2-one
(VII, EXAMPLE 14), the title compound is obtained, mp 166-168.
EXAMPLE 16
(.+-.)-3-(5'-1-Carbo-t-butyloxyindolinyl)-5-(acetamidomethyl)oxazolidin-2-o
ne (IX)
Following the general procedure of EXAMPLE 8 and making
non-critical variations but starting with
(.+-.)-3-(5'-1-carbo-t-butyloxyindolinyl)-5-(aminomethyl)oxazolidin-2-one
(VIII, EXAMPLE 17), the title compound is obtained, mp
139.degree.-140.degree..
EXAMPLE 17
(.+-.)-3-(5'-Indolinyl)-5-(acetamidomethyl)oxazolidin-2-one (X)
Trifluoroacetic acid (0.250 ml) is added slowly over one minute to
a mixture of (.+-.)-3-(5'-1-carbo
-t-butyloxyindolinyl)-5-(acetamidomethyl)oxazolidin-2-one (IX,
EXAMPLE 16, 0.038 mg) in methylene chloride (3 ml). The mixture is
stirred for 1.5 hr under nitrogen then poured into saturated
aqueous sodium bicarbonate 930 ml). The aqueous mixture is
extracted with methylene chloride (3.times.for a total of 40 ml).
The combined organic extracts are washed with saturated aqueous
sodium bicarbonate 910 ml) and the aqueous extracts combined. The
combined aqueous extracts are extracted again with methylene
chloride (5.times. for a total of 50 ml). The combined organic
extracts are dried over magnesium sulfate and concentrated under
reduced pressure to give the title compound, MS (m/e) 275, 231,
172, 159 and 147; exact mass clacd for C.sub.14 H.sub.17 N.sub.3
O.sub.3 =275.1270, found 175.1282.
EXAMPLE 18
(.+-.)-3-(5'-1-Isobutyrlindolinyl]-5-(acetamidomethyl)oxazolidin-2-one
(XI)
(.+-.)-3-(5'-Indolinyl)-5-acetamidomethyl)oxazolidin-2-one (X,
EXAMPLE 17, 53 mg) is dissolved in methylene chloride (1.0 ml).
Triethylamine (80 .mu.l) is added. Isobutyrl chloride (25 .mu.l) is
added slowly over 30 seconds at 0.degree.. After stirring for two
hr, the mixture is added to saline (10 ml) and extracted with
methylene chloride (6.times. for 20 ml total). The combined organic
extracts are dried over magnesium sulfate and concentrated to
provide a solid. The solid is purified by passing thru a silica
cartridge, eluting with chloroform (1 ml) ethyl acetate (4 ml),
methanol/ethyl acetate (10/90, 27 ml). The appropriate fractions
are pooled and concentrated to give the title compound, mp
200.degree.-202.degree..
EXAMPLES 19-24
Following the general procedure of EXAMPLE 18 and making
non-critical variations but using the appropriate R.sub.5 group the
compounds of EXAMPLES 19-24 are obtained:
______________________________________ EX- AMPLE Compound Obtained
______________________________________ 19
(.+-.)-3-(5'-1-Propanoylindolinyl)-5-(acetamidomethyl)-
oxazolidin-2-one (XI), 20
(.+-.)-3-(5'-1-Cyclopentylcarbonylindolinyl)-5-(acet-
amidomethyl)oxazolidin-2-one (XI), 21
(.+-.)-3-(5'-1-Formylindolinyl)-5-(acetamidomethyl)-
oxazolidin-2-one (XI), 22
(.+-.)-3-(5'-1-Chloroacetylindolinyl-5-(acetamido-
methyl)oxazolidin-2-one (XI), 23
(.+-.)-3-(5'-1-Dichloroacetylindolinyl)-5-(acetamido-
methyl)oxazolidin-2-one (XI) and 24
(.+-.)-3-(5'-1-Phenylacetylindolinyl)-5-(acetamido-
methyl)oxazolidin-2-one (XI)
______________________________________
EXAMPLE 25
1-Carbo-t-butyloxy-6-nitroindoline (II)
Di-tert-butyldicarbonate (11.500 g) is added to a mixture of
6-nitroindoline (I, 4.300) in freshly distilled THF (40 ml). The
mixture is refluxed for 3 days then poured into water (125 ml) and
extracted with ethyl acetate (3.times., 220 ml total). The combined
organic layers are washed with aqueous sodium bicarbonate (5%),
saline, dried over magnesium sulfate and concentrated under reduced
pressure to obtain a mixture of a solid in an oil. This mixture is
recrystallized with acetone/water to give the title compound, mp
104.degree.-105.degree.; NMR (CDCl.sub.3, 300 MHz) 8.5-8.1, 7.71,
7.14, 4.00, 3.10 and 1.51 .delta.; CMR (CDCl.sub.3, 75.47 MHz)
27.12, 28.16, 47.94, 77.2, 81.3, 109.28, 117.51, 124.45, 138.4,
143.6, 147.84 and 151.92 .delta.; IR (CHCl.sub.3) 1695, 1480, 1385,
1340 and 1140 cm.sup.-1 ; MS (m/e) 264, 208, 191, 164, 118 and
57.
EXAMPLE 26
1-Carbo-t-butyloxy-6-aminoindoline (III)
Palladium on carbon (10%, 1.198 g) is added to a mixture of
1-carbo-t-butyloxy-6-nitroindoline (II, EXAMPLE 25, 5.311 g) in
ethyl acetate (freshly open bottle, 500 ml) at 0.degree.. The
mixture is stirred under 1 atm hydrogen (balloon) at
20.degree.-25.degree. for 7 hr. The mixture is then filtered and
concentrated under reduced pressure to give the title compound, mp
151.degree.-152.degree.; NMR (CDCl.sub.3, 300 MHz) 7.29, 6.80,
6.25, 3.93, 3.61 and 2.95 .delta.; CMR (CDCl.sub.3, 75.47 MHz)
26.58, 28.47, 48.29, 80.2, 102.50, 108.77, 120.9, 124.94, 146.13
and 152.9 .delta.; IR (CHCl.sub.3) 3380, 3460, 1690, 1620, 1490,
1450 and 1390 cm.sup.-1.
EXAMPLE 27
1-Carbo-t-butyloxy-(N-carbobenzyloxy)-6-aminoindoline (IV)
Following the general procedure of EXAMPLES 3 and 11 and making
non-critical variations but starting with
1-carbo-t-butyloxy-6-aminoindoline (III, EXAMPLE 26), the title
compound is obtained, MS (m/e) 368, 312, 268, 91 and 57; exact mass
calcd for C.sub.21 H.sub.24 N.sub.2 O.sub.4 =368.1736, found
368.1737.
EXAMPLE 28
1-Carbo-t-butyloxy-(N-allyl-N-carbobenzyloxy)-6-amino-indoline
(V)
Following the general procedure of EXAMPLES 4 and 12 and making
non-critical variations but starting with
1-carbo-t-butyloxy-(N-carbobenzyloxy)-6-aminoindoline (IV, EXAMPLE
27), the title compound is obtained, MS (m/e) 408, 352, 308, 217,
91 and 57; exact mass calcd for C.sub.24 H.sub.28 N.sub.2 O.sub.4
=408.2049, found 408.2073.
EXAMPLE 29
(.+-.)-3-(6'-1-Carbo-t-butyloxyindolinyl)-5-(iodomethyl)oxazolidin-2-one
(VI)
Following the general procedure of EXAMPLES 5 and 13 and making
non-critical variations but starting with
1-carbo-t-butyloxy-(N-allyl-N-carbobenzyloxy)-6-aminoindoline (V,
EXAMPLE 28), the title compound is obtained, MS (m/e) 444, 388,
344, 217, 173, 57 and 41; exact mass calcd for C.sub.17 H.sub.1
N.sub.2 O.sub.4 =444.0548, found 444.0560.
EXAMPLE 30
(.+-.)-3-(6'-1-Carbo-t-butyloxyindolinyl)-5-(azidomethyl)oxazolidin-2-one
(VII)
Following the general procedure of EXAMPLES 6 and 14 and making
non-critical variations but starting with
(.+-.)-3-(6'-1-carbo-t-butyloxyindolinyl)-5-(iodomethyl)oxazolidin-2-one
(VI, EXAMPLE 29), the title compound is obtained, MS (m/e) 359,
303, 259, 186, 160 and 57; exact mass calcd for C.sub.17 H.sub.21
N.sub.5 O.sub.4 =359.1593, found 359.1605.
EXAMPLE 31
(.+-.)-3-(6'-1-Carbo-t-butyloxyindolinyl)-5-(aminomethyl)oxazolidin-2-one
(VIII)
Following the general procedure of EXAMPLES 7 and 15 and making
non-critical variations but starting with
(.+-.)-3-(6'-1-carbo-t-butyloxyindolinyl)-5-(azidomethyl)oxazolidin-2-one
(VII, EXAMPLE 30), the title compound is obtained, MS (m/e) 333,
277, 233, 147 and 57; exact mass clacd for C.sub.17 H.sub.23
N.sub.3 O.sub.4 =333.1688, found 333.1692.
EXAMPLE 32
(.+-.)-3-(6'-1-Carbo-t-butyloxyindolinyl)-5-(acetamidomethyl)oxazolidin-2-o
ne (IX)
Following the general procedure of EXAMPLES 8 and 16 and making
non-critical variations but starting with
(.+-.)-3-(6'-1-carbo-t-butyloxyindolinyl)-5-(aminomethyl)oxazolidin-2-one
(VIII, EXAMPLE 31), the title compound is obtained, MS (m/e) 375,
275, 148, 134 and 57; exact mass clacd for C.sub.19 H.sub.25
N.sub.3 O.sub.5 =375.1794, found 375.1803.
EXAMPLE 33
(.+-.)-3-(6'-Indolinyl)-5-(acetamidomethyl)oxazolidin-2-one (X)
Following the general procedure of EXAMPLE 17 and making
non-critical variations but starting with
(.+-.)-3-(6'-1-carbo-t-butyloxyindolinyl)-5-(acetamidomethyl)oxazolidin-2-
one (IX, EXAMPLE 32), the title compound is obtained, mp
60.degree.-62.degree..
EXAMPLES 34-38
Following the general procedure of EXAMPLE 18 and making
non-critical variations but starting with
(.+-.)-3-(6'-indolinyl)-5-(acetamidomethyl)oxazolidin-2-one (X,
EXAMPLE 33) and using an acylating agent to provide the appropriate
R.sub.5 group the compounds of EXAMPLES 34-38 are obtained:
______________________________________ EX- AMPLE Compound Obtained
______________________________________ 34
(.+-.)-3-(6'-1-Acetylindolinyl)-5-(acetamidomethyl)-
oxazolidin-2-one (XII), 35
(.+-.)-3-(6'-1-Isobutyrlindolinyl)-5-(acetamidomethyl)-
oxazolidin-2-one (XII), 36
(.+-.)-3-(6'-1-Propanoylindolinyl)-5-(acetamidomethyl)-
oxazolidin-2-one (XII), 37
(.+-.)-3-(6'-1-Cyclopentanecarbonylindolinyl)-5-(acet-
amidomethyl)oxazolidin-2-one (XII) and 38
(.+-.)-3-(6'-1-Formylindolinyl)-5-(acetamidomethyl)-
oxazolidin-2-one (XII) ______________________________________
EXAMPLE 39
(.+-.)-3-(5'-1-allylindolinyl)-5-(N-acetamidomethyl)oxazolidin-2-one
(XI)
Following the general procedure of EXAMPLE 18 and making
non-critical variations but using allyl bromide the title compound
is obtained.
EXAMPLE 40
(.+-.)-3-(6'-indolinyl)-5-(acetamidomethyl)oxazolidin-2-one (X,
EXAMPLE 33) and using allyl bromide the title compound is
obtained.
EXAMPLE 41
N-(Carbobenzyloxy)-5-aminoindan (XVIA)
Sodium bicarbonate 97.20 g) is added to a solution of 5-aminoindan
(XVA, 5.71 g) in acetone (60 ml) and water (30 ml) 0.degree.,
followed by the dropwise addition of benzylchloroformate 96.8 ml,
8.07 g) over 5 min. The mixture is stirred at 0.degree. for about 1
hr, then at 20.degree.-25.degree. overnight. The mixture is poured
into aqueous sodium hydrogen sulfate (10%, 200 ml), and ethyl
acetate (300 ml). The organic extract is washed with saturated
aqueous sodium bicarbonate, dried over magnesium sulfate, and
concentrated under reduced pressure to give an oil. The oil is
purified by column chromatography on 60-200.mu. silica gel, eluting
with ethyl acetate/hexane (10/90). The appropriate fractions are
pooled and concentrated to give the title compound, mp
56.degree.-59.degree.; NMR (CDCl.sub.3, 300 MHz) 7.40-7.03, 7.11,
7.05, 6.65, 5.18, 2.85 and 2.05 .delta.; IR (mineral oil mull)
3275, 2925, 1693.5, 1544 and 1236 cm.sup.-1 ; MS (m/e) 267, 223,
222 and 91.
EXAMPLE 42
N-(Carbobenzyloxy)-N-(allyl)-5-aminoindan (XVIIA)
A sodium hydride/mineral oil dispersion (50%, 2.00 g) is carefully
added to a solution of N-(carbobenzyloxy)-5-aminoindan (XVIA,
EXAMPLE 41, 8.856 g) in freshly distilled tetrahydrofuran (about
350 ml) at 20.degree. under argon. The reaction is mildly
exothermic with evolution of hydrogen gas. Allyl bromide (3.4 ml,
4.8 g) is then added over 1 min. The mixture is stirred at
20.degree.-25.degree. for 1 hr forming a solid. The mixture is then
heated at reflux for 3.5 hr then stirred at 20.degree.-25.degree.
overnight. An aliquot is taken, poured into water and ethyl
acetate, and the organic layer evaporated. NMR analysis indicates
complete reaction. The mixture is poured into ethyl acetate (300
ml), and washed with water (2.times.250 ml). The combined aqueous
layers are extracted with ethyl acetate (100 ml). The combined
organic layers are washed with saline, dried over magnesium sulfate
and concentrated under reduced pressure to give an oil. The residue
is purified by gravity filtration thru a silica gel column (2.5
cm.times.10 cm, 60-200.mu.), eluting with hexane. The appropriate
fractions are pooled and concentrated to give the title compound as
an oil. An analytical sample is obtained by MPLC using ethyl
acetate/hexane (10/90). NMR (CDCl.sub.3, 300 MHz) 7.30, 7.16, 7.06,
6.96, 5.91, 5.16, 5.13, 4.24, 2.88 and 2.08 .delta.; IR
(CHCl.sub.3) 2944, 1694, 1400 and 1153 cm.sup.-1 ; MS (m/e) 307,
263, 248, 172, 144 and 91, exact mass calculated for C.sub.20
H.sub.21 NO.sub.2 =307.1572, found 307.1565.
EXAMPLE 43
(.+-.)-3-(5'-Indanyl)-5-(iodomethyl)oxazolidin-2-one (XVIIIA)
Iodine (16.84 g) is added to a solution of
3-(carbobenzyloxy)-N-(allyl)-5-aminoindan (XVIIA, EXAMPLE 42, 10.39
g) in chloroform (400 ml) at 20.degree.. The mixture is stirred at
20.degree. for 3.3 hr, then poured into aqueous sodium thiosulfate
(10%, 550 ml). The layers are separated and the chloroform layer is
dried over magnesium sulfate and concentrated under reduced
pressure to give a solid. The solid is retained at 0.1 Torr for 18
hr to give crystals which are recrystallized from acetone (300 ml)
and water (240 ml) to give after drying under reduced pressure at
70.degree. a solid. Analysis by NMR shows this material to contain
a trace of mineral oil. From the mother liquors additional product
is obtained. For analysis, a small sample is chromatographed on
silica gel eluting with ethyl acetate/hexane (10/90), concentrated
and then recrystallized as above to give the title compound, mp
104.degree.-105.degree.; NMR (CDCl.sub.3, 300 MHz) 7.44, 7.21,
4.69, 4.15, 3.76, 3.45, 3.34, 2.90 and 2.08.delta.; CMR (75.47 MHz,
CDCl.sub.3) 6.07, 25.39, 32.05, 32.86, 51.29, 70.93, 115.04,
116.56, 124.40, 135.76, 140.38 and 145.22 .delta.; IR (mineral oil
mull) 2922, 1728, 1485 and 1420 cm.sup.-1 ; MS (m/e) 343, 215, 172,
144, 117 and 91, exact mass calculated for C.sub.13 H.sub.14
INO.sub.2 =343.0071, found 343.0066.
EXAMPLE 44
(.+-.)-3-(5'-Indanyl)-5-(azidomethyl)oxazolidin-2-one (XIXA)
Sodium azide (5.30 g) in water (50 ml) is added to a solution of
(.+-.)-3-(5'-indanyl)-5-(iodomethyl) oxazolidin-2-one (XVIIIA,
EXAMPLE 43, 3.726 g, 10.86 mmol) in acetone (250 ml). The mixture
is heated at reflux behind a safety shield for 27 hr, stirred at
20.degree.-25.degree. overnight, then poured into water (350 ml)
and extracted with ethyl acetate (3.times.175 ml). The combined
extracts are washed with water (50 ml), followed by saline (50 ml),
dried over magnesium sulfate and concentrated under reduced
pressure (safety shield) to give an oil, which on standing at
0.degree. crystallized. NMR analysis indicates the title compound
with only a small amount of residual mineral oil; this material is
used without attempted upgrading. NMR (CDCl.sub.3, 300 MHz) 7.46,
7.22, 4.76, 4.09, 3.86, 3.68, 3.58, 2.90 and 2.09 .delta.; IR
(CHCl.sub.3) 2120, 1760, 1489 and 1410 cm.sup.-1 ; MS (m/e) 258,
230, 201, 185, 170, 158, 144, 130 and 117, exact mass calculated
for C.sub.13 H.sub.14 N.sub.4 O.sub.2 =258.1117, found
258.1132.
EXAMPLE 45
(.+-.)-3-(5'-Indanyl)-5-(aminomethyl)oxazolidin-2-one (XXA)
A solution of (.+-.)-3-(5'-indanyl)-5-(azidomethyl)oxazolidin-2-one
(XIXA, EXAMPLE 44, 3.05 g, slightly impure) in ethyl acetate (600
ml, freshly opened, Fisher HPLC grade), is evacuated (20 Torr) and
filled with argon (4.times.). Then palladium/carbon (10%, 1.276 g)
is added, and the system evacuated and filled with hydrogen from a
balloon (4.times.). The mixture was stirred at
20.degree.-25.degree. for 19 hr. TLC analysis shows a trace of
starting material, so more hydrogen is added via a fresh balloon.
After stirring an additional 2.25 hr, the mixture is filtered thru
diatomaceous earth, washing the pad first with ethyl acetate, then
methanol/ethyl acetate (10/90). The filtrate is concentrated under
reduced pressure to give a solid. This is deemed of sufficient
quality for further use.
For an analytical sample, approximately 50 mg is dissolved in
chloroform and loaded onto a 2 inch silica gel plug in a pipette.
This is eluted with ethyl acetate to remove less polar impurities,
then methanol/ethyl acetate (1/1). The elute is concentrated to
give the title compound, mp 101.degree.-103.degree.; NMR
(CDCl.sub.3, 300 MHz) 7.45, 7.21, 4.65, 4.03, 3.81, 3.07, 2.99,
2.89, 2.07 and 1.58 .delta.; CMR (CDCl.sub.3, 75.47 MHz) 25.55,
32.19, 33.02, 45.06, 48.15, 73.73, 115.00, 116.52, 124.47, 136.36,
140.16 and 145.27 .delta.; IR (CHCl.sub.3) 3688, 3390, 1745, 1614,
1484 and 1404 cm.sup.-1 ; MS (m/e) 232, 203, 187, 171, 159 and 146,
exact mass calculated for C.sub.13 H.sub.16 O.sub.2 N.sub.2
=232.1212, found 232.1214.
EXAMPLE 46
(.+-.)-3-(5'-Indanyl)-5-(acetamidomethyl)oxazolidin-2-one
(XXIA)
Acetic anhydride (1.5 ml) is added to a solution of
(.+-.)-3-(5'-indanyl)-5-(aminomethyl) oxazolidin-2-one (XXA,
EXAMPLE 45, 0472 g) in pyridine (3.0 ml) over a period of 2 min
with a slight exotherm. The mixture is stirred at
20.degree.-25.degree. for 21 hr, then concentrated under reduced
pressure to give an oil. The oil is transferred to a Erlenmeyer
flask (50 ml) containing chloroform (10 ml) and ethyl acetate 920
ml) is added. The mixture is concentrated under a gentle nitrogen
flow to give the title compound, mp 133.degree.-134.degree.; NMR
(CDCl.sub.3, 300 MHz) 7.37, 7.19, 7.06, 4.74, 4.02, 3.78, 3.60,
2.87, 2.06 and 2.00 .delta.; CMR (CDCl.sub.3, 75.47 MHz) 22.94,
25.60, 32.25, 33.04, 41.86, 48.12, 72.00, 115.28, 116.91, 124.58,
136.09, 140.54, 145.34, 154.98, 171.44 .delta.; IR (mineral oil
mull) 3344, 2925, 1739, 1663, 1551 and 1419 cm.sup.-1 ; MS (m/e)
274, 230, 215, 202, 187, 171, 170, 158, 146, 133 and 117 exact mass
calculated for C.sub.15 H.sub.18 N.sub.2 O.sub.3 =274.1317, found
274.1322.
EXAMPLE 47
(.+-.)-3-(5' -Indanyl)-5-(butyramidomethyl)oxazolidin-2-one
(XXIA)
Following the general procedure of EXAMPLE 46 and making
non-critical variations but starting with butyric anhydride, the
title compound is obtained, NMR (CDCl.sub.3, 300 MHz) 7.39, 7.20,
6.5, 4.75, 4.03, 3.78, 3.64, 2.88, 2.19, 2.08 and 1.63 .delta.; CMR
(CDCl.sub.3, 75.47 MHz) 13.53, 18.91, 25.44, 32.11, 32.90, 38.22,
41.68, 47.96, 71.76, 115.04, 116.64, 124.43, 136.1, 140.6, 145.5,
155.0 and 174.0 .delta.; IR (mineral oil mull) 3349, 2959, 2927,
2855, 1736, 1656, 1544, 1495, 1468 and 1420 cm.sup.-1 ; MS (m/e)
302, 274, 258, 215, 202, 187, 171, 146 and 133, exact mass
calculated for C.sub.17 H.sub.22 N.sub.2 O.sub.3 =302.1630, found
302.1633.
EXAMPLE 48
(.+-.)-3-(5'-Indanyl)-5-(cyclopropylcarboxamido)methyloxazolidin-2-one
(XXIA)
Triethylamine (0.139 g, 0.19 ml) is added to a mixture of
(.+-.)-3-(5'-indanyl)-5-(aminomethyl)oxazolidin -2-one (XXA,
EXAMPLE 45, 0.236 g) in methylene chloride (5.0 ml). The mixture is
cooled to 0.degree. under argon, and then cyclopropane carbonyl
chloride (0.143 g, 0.125 ml) is added dropwise over about 7 min.
The mixture is stirred at 0.degree. for 30 min, then allowed to
warm to 20.degree.-25.degree.. TLC analysis indicates complete
conversion, and the mixture is concentrated under reduced pressure.
The solid residue is purified by column chromatography on silica
gel (60-200.mu., 11 cm.times.2.5 cm, 25 ml fractions), loading as a
solution in chloroform, then eluting with ethyl acetate. The
appropriate fractions are poled to give the title compound, mp
145.degree.-147.degree.; NMR (CDCl.sub.3, 300 MHz) 7.40, 7.195,
7.20, 6.55, 4.75, 4.02, 3.79, 3.67, 2.88, 2.075, 1.42, 0.92 and
0.74 .delta.; CMR (CDCl.sub.3, 75.47 MHz) 7.52, 7.62, 14.54, 25.61,
32.26, 33.06, 42.01, 48.13, 72.03, 115.32, 116.92, 124.58, 136.16,
140.60, 145.48, 154.91 and 174.89 .delta.; IR (mineral oil mull)
3305, 2954, 2924, 2854, 1746, 1666, 1554, 1496 and 1422 cm.sup.-1 ;
MS (m/e) 300, 256, 241, 215, 202, 185, 171, 158, 146 and 133, exact
mass calculated for C.sub.17 H.sub.20 N.sub.2 O.sub.3 =300.1474,
found 300.1480.
EXAMPLE 49
(.+-.)-3-(5'-Indanyl)-5-(formylamidomethyl)oxazolidin-2-one
(XXIA)
A mixture of (.+-.)-3-(5'-indanyl)-5-(aminomethyl)oxazolidin-2-one
(XXA, EXAMPLE 45, 0.139 g) in formic acid (1.0 ml) and acetic
anhydride (0.2 ml) is stirred at 20.degree. for 2 days, then
concentrated under reduced pressure to give a brown oil, NMR
analysis indicates clean conversion. The residue is taken up in
chloroform and ethyl acetate and the mixture is concentrated under
a stream of nitrogen to give the title compound; NMR (CDCl.sub.3,
300 MHz) 8.23, 7.36, 7.19, 7.04, 4.76, 4.03, 3.80, 3.77-3.58, 2.87
and 2.05 .delta.; CMR (CDCl.sub.3) 25.60, 32.26, 33.05, 40.28,
48.12, 71.68, 115.40, 117.03, 124.64, 135.90, 140.77, 145.44, 154.6
and 162.3 .delta.; IR (CHCl.sub.3) 3430, 3315, 1750, 1689 and 1482
cm.sup.-1 ; MS (m/e) 260, 216, 202, 170, 158, 146, 133 and 117;
exact mass calculated for C.sub.14 H.sub.16 N.sub.2 O.sub.3
=260.1161, found 260.1174.
EXAMPLE 50
(.+-.)-3-(5'-Indanyl)-5-(benzamidomethyl)oxazolidin-2-one
(XXIA)
Benzoyl chloride (0.31 g, 0.26 ml) is added to a solution of
(.+-.)-3-(5'-indanyl)-5-(aminomethyl) oxazolidin-2-one (XXA,
EXAMPLE 45, 0.518 g) in pyridine (4.0 ml) at 0.degree. under argon
over a period of 1 min. The mixture is stirred at 0.degree. for
about 1 hr, then allowed to warm to 20.degree.-25.degree. for a
total of 23 hr. TLC analysis shows residual starting materials, so
benzoyl chloride (0.1 ml) is added after again cooling to
0.degree., and after 5 hr the reaction is complete. The mixture is
concentrated under reduced pressure to give an oil with crystals.
This material is chromatographed using MPLC (2.5 cm.times.22 cm
silica gel, 40-63.mu., with a gradient elution with 25%, 50%, 75%,
and 100% ethyl acetate/hexane). The appropriate fractions are
pooled and concentrated to give the tile compound, mp
159.5.degree.-161.degree.. For analysis, a portion is dissolved in
chloroform and ethyl acetate and concentrated under a stream of
nitrogen to provide crystalline material, NMR (CDCl.sub.3, 300 MHz)
7.81, 7.78, 7.47, 7.37, 7.26, 7.18, 7.15, 4.84, 4.06, 3.92-3.72,
2.85 and 2.04 .delta.; CMR (CDCl.sub.3, 75.47 MHz) 25.50, 32.16,
32.95, 42.52, 48.26, 71.93, 115.24, 116.84, 124.49, 127.09, 128.47,
131.72, 133.56, 135.97, 140.47, 145.26, 154.80 and 168.29 .delta.;
IR (mineral oil mull) 3367, 2949, 2915, 1757, 1654, 1551, 1491 and
1408 cm.sup.-1 ; MS (m/e) 336, 292, 215, 202, 187, 171, 158, 146,
133 and 105, exact mass calculated for C.sub.20 H.sub.20 N.sub.2
O.sub.3 =336.1474, found 336.1472.
EXAMPLE 51
(.+-.)-3-(5'-Indanyl)-5-(methoxycarboxamidomethyl)oxazolidin-2-one
(XXIA)
Triethylamine (56 .mu.l) followed by methyl chloroformate (36
.mu.l) is added to a mixture
(.+-.)-3-(5'-indanyl)-5-(aminomethyl)oxazolidin-2-one (XXA, EXAMPLE
45, 0.085 g) in methylene chloride (3.0 ml) under argon at
0.degree.. The mixture is stirred at 0.degree. for 45 min, then
allowed to warm to 20.degree.-25.degree.. After a total of 19 hr,
the mixture is concentrated under reduced pressure to give a
residue. The residue is purified by gravity chromatography through
a short silica gel column in a pipette (2"), loading with
chloroform, and then eluting with ethyl acetate/hexane (1/1). The
eluate is concentrated to give the title compound, NMR (CDCl.sub.3,
300 l MHz) 7.42, 7.20, 5.31, 4.74, 4.04, 3.79, 3.68, 3.61-3.46,
2.90 and 2.08 .delta.; CMR (CDCl.sub.3, 75.47 MHz) 25.63, 32.27,
33.08, 43.75, 47.97, 52.54, 71.71, 115.19, 116.74, 124.59, 136.15,
140.50, 145.41, 154.9 and 157.7 .delta..
EXAMPLE 52
(.+-.)-3-(1'-Oxo-5'-indanyl)-5-(acetamidomethyl)oxazolidin-2-one
(XXIB)
A solution of chromium trioxide (1.09 g) dissolved in glacial
acetic acid (14ml) and water (4 ml) is added to a solution of
(.+-.)-3-(5'-indanyl)-5-(acetamidomethyl)oxazolidin-2-one (XXIA,
EXAMPLE 46, 1.198 g) in glacial acetic acid (25 ml) and acetic
anhydride (4 ml) at 20.degree.-25.degree.. A mild exotherm is
observed. The mixture is stirred at 20.degree.-25.degree. for 2 hr,
then poured into ice (250 g) and allowed to stand for 20 min. The
pH is then adjusted by the careful addition of saturated aqueous
sodium bicarbonate to 7-7.5. The mixture is extracted with ethyl
acetate 95.times.200 ml), then with methylene chloride (3.times.200
ml). The extracts are washed with saline, dried over magnesium
sulfate, and concentrated under reduced pressure to give an oil.
The oil is taken up in chloroform and concentrated under reduced
pressure to give a solid. A portion of the solid is purified by
silica gel flash chromatography (0.5.times.5 cm column, eluting
with chloroform, then ethyl acetate, followed by a gradient of
methanol-ethyl acetate. The appropriate factions are pooled to give
the tile compound, NMR (CDCl.sub.3 300 MHz) 7.71, 7.65, 7.51, 6.77,
4.84, 4.13, 3.90, 3.70, 3.12, 2.69, and 2.0 .delta.; CMR
(CDCl.sub.3, 75.47 MHz) 23.06, 25.96, 36.41, 41.80, 47.63, 72.20,
115.03, 117.08, 124.67, 132.74, 143.56, 154.25, 156.74, 171.45 and
205.74 .delta.; IR (CHCl.sub.3) 3440, 1757, 1694, 1605, 1480, 1400,
1280, and 1130 cm.sup.-1 ; MS (m/e) 288, 244, 229, 216, 201, 185,
160 and 147; exact mass calcd for C.sub.15 H.sub.16 O.sub.4 N.sub.2
=288.1110, found 288.1101.
EXAMPLE 53
(.+-.)-3-(1-Oximini-5'-indanyl)-5-(acetamidomethyl)oxazolidin-2-one
(XXIE)
A mixture of
(.+-.)-3-(1'-oxo-5'-indanyl)-5-(acetamidomethyl)oxazolidin-2-one
(XXIB, EXAMPLE 52, 0.172 g) and hydroxylamine hydrochloride (0.448
g) in methanol (10 ml) and water (5 ml) is stirred at
20.degree.-25.degree.. Then saturated aqueous sodium bicarbonate
(12.5 ml) is slowly added over about 10 min. The mixture is stirred
for 19 hr, then poured into water (50 ml) and extracted with ethyl
acetate (2.times.40 ml, then 2.times.25 ml) and then methylene
chloride (6.times.25 ml). The organic extracts are washed with
saline, dried over magnesium sulfate and concentrated under reduced
pressure to give a solid as a mixture of syn and anti isomers; mp
144.degree.-160.degree.; Major isomer: NMR (CDCl.sub.3 +CD.sub.3
OD, 300 MHz) 7.65, 7.54, 7.44, 4.8, 4.16, 3.85, 3.59, 3.06, 2.94,
and 200 .delta.; minor isomer (unobscured peaks; relative ratio to
major isomer=1:5.6) 8.42, 7.73, 4.23, 3.92, 3.19, 2.84, and 2.72;
IR (mineral oil mull) 3293, 1746, 1657, 1408, and 1225
cm.sup.-1.
EXAMPLE 54
(.+-.)-3-(1'-Hydroxy-5'-indanyl)-5-(acetamidomethyl)oxazolidin-2-one
(XXIC)
Sodium borohydride (0.023 g) is added to a solution of
(.+-.)-3-(1'-oxo-5'-indanyl)-5-(acetamidomethyl) oxazolidin-2-one
(XXIB, EXAMPLE 52, 0.044 g) in absolute ethanol (5 ml) at
20.degree.-25.degree.. The mixture is stirred for 2.5 hr, then
analyzed by TLC. Additional sodium borohydride (0.026 g) is added.
After a total of 22 hr, acetone is added, and the mixture
concentrated to 1/2 volume, then poured into dilute aqueous
hydrochloric acid (0.25N, 6 ml in 20 ml water), and the mixture
extracted with ethyl acetate (5.times.10 ml). The combined organic
extracts are washed with saturated aqueous sodium bicarbonate,
dried over magnesium sulfate and concentrated under reduced
pressure to give an oil. Additional material is recovered by
continued extraction of the aqueous layer with ethyl acetate. A 10
mg sample is chromatographed on silica gel (4 cm.times.0.5 cm,
40-63.mu.), eluting with a gradient of ethyl acetate-methanol. The
appropriate fractions are pooled and concentrated to give the title
compound as a mixture of diastereomers A and B, and of the more
polar diastereomer B, as oils. Diastereomeric mixture NMR
(CDCl.sub. 3, 300 HMz) 7.5-7.3, 6.60, 5.21, 4.73, 4.03, 3.76, 3.62,
3.02, 2.80, 2.46, 2.00, and 1.95 .delta.; IR (CHCl.sub.3) 3680,
3600, 3440, 1750, 1674, and 1405 cm.sup.-1 ; MS exact mass calcd
for C.sub.15 H.sub.18 O.sub.4 N.sub.2 =290.1226, found
290.1277.
EXAMPLE 55
(.+-.-3-(6'-Tetralinyl)-5-(acetamidomethyl)oxazolidin-2one
(XXIA)
Following the general procedure of EXAMPLES 41-46 and making
non-critical variations but starting with 6-aminotetralin, the
title compound is obtained.
EXAMPLE 56
(+)-3-(1'-Oxo-6'-tetralinyl)-5-(acetamidomethyl)oxazolidin-2-one
(XXIB)
Following the general procedure of EXAMPLE 52 and making
non-critical variations but starting with
(.+-.)-3-(6'-tetralinyl)-5-(acetamidomethyl)oxazolidin-2-one (XXIA,
EXAMPLE 55), the title compound is obtained.
EXAMPLE 57
1-Carbo-t-butyloxy-5-nitroindazole (XXIII)
A mixture of 5-nitroindazole (XXII, 5.685) and di-t-butyl
dicarbonate (15.325 g) is stirred for four days in refluxing THF
(freshly distilled, 220 ml) under nitrogen. The mixture is then
concentrated to 70 ml, by distillation, and then poured over
crushed ice (600 ml). After the ice melts, the mixture is filtered
using reduced pressure. The precipitate is dried in a vacuum oven
to give a solid. A small amount (536 mg) of this product is
purified by passing it through a silica gel column (23.5.times.2.5
cm, 40-63.mu.) eluting with ethyl acetate/hexane (1/3. 700 ml and
then 1/1 200 ml). The appropriate fractions are pooled and
concentrated to a solid. The solid is recrystallized from acetone
to give the title compound, NMR (CDCl.sub.3, 300 MHz) 8.71,
8.43-8.32 and 1.76 .delta.; CMR (CDCl.sub.3 75.47 MHz) 27.91,
86.19, 114.956, 117.82, 123.54, 125.27, 140.06, 141.79, 144.08 and
148.30 .delta.; IR (mineral oil mull) 1765, 1736, 1532, 1383, 1347,
1291, 1155 and 1151 cm.sup.-1 ; MS (m/e) 263, 204, 163, 57 and
40.
EXAMPLE 58
1-Carbo-t-butyloxy-5-aminoindazole (XXIV)
To a solution of 1-carbo-t-butyloxy-5-nitroindazole (XXIII, EXAMPLE
57, 6.165 g) in ethyl acetate (:125 ml) is added palladium on
carbon (10%, 734 mg). The mixture is stirred under hydrogen (1 atm.
balloon) at 20.degree.-25.degree.. After stirring for 27 hours,
more palladium on carbon (10%, 294 mg) is added. Then, after
stirring for an additional two days under hydrogen, the mixture is
filtered over dicalite and the filtrate is concentrated to an oil.
The oil is taken up in ethyl acetate (125 ml), dried over magnesium
sulfate and concentrated to an oil. The oil is passed over a silica
column (27.times.4.5 cm, 40-63.mu.) eluting with ethyl
acetate/hexane (1/3, 500 ml followed by 1/1 1000 ml), ethyl acetate
(1000 ml) and methanol/ethyl acetate (1/9, 1000 ml). The
appropriate fractions are pooled and concentrated to give the title
compound, NMR (CDCl.sub.3, 300 MHz) 7.99-7.94, 6.97-6.91, 3.77 and
1.71 .delta.; CMR (CDCl.sub.3, 75.47 MHz) 28.06, 84.335, 103.82,
115.05, 119.35, 126.84, 134.07, 138.68, 142.64 and 149.13 .delta.;
IR (mineral oil mull) 1736, 1518, 1462, 1375, 1301, 1232 and 1145
cm.sup.-1 ; MS (m/e) 233, 133, 105, 57 and 40.
EXAMPLE 59
1-Carbo-t-butyloxy-5-(N-carbobenzyloxy)aminoindazole (XXV)
Benzyl chloroformate (2.45 ml) is added to a mixture of
1-carbo-t-butyloxy-5-aminoindazole (XXIV, EXAMPLE 58, 3.760 g) and
sodium bicarbonate (2.721 g) in acetone/water (1/1, 50 ml) at
0.degree. over one minute. The mixture is stirred under nitrogen
for 1.5 hr then poured into water (50 ml). The aqueous mixture is
then extracted with ethyl acetate (3.times., 250 ml total). The
combined organic layers are washed with aqueous sodium bisulfate
(10%, 125 ml), aqueous sodium bicarbonate (10%, 125 ml), saline
(125 ml), dried over magnesium sulfate, and concentrated to a give
the title compound as a solid, NMR (CDCl.sub.3, 300 MHz) 8.08-7.98,
7.48-7.27, 5.20 and 1.70 .delta.; CMR (CDCl.sub.3, 75.47 MHz)
28.03, 66.99, 84.82, 109.7, 114.77, 121.1, 126.19, 128.19, 128.26,
128.50, 133.93, 135.84, 136.20, 139.32, 149.00 and 153.59 .delta.;
IR (mineral oil mull) 1746, 1726, 1521, 1395, 1355, 1290, 1218 and
1044 cm.sup.-1 ; MS (m/e) 367, 267, 223, 132, 91, 57 and 40.
EXAMPLE 60
1-Carbo-t-butyloxy-5-(N-allyl-N-carbobenzyloxy)aminoindazole (XXVI)
1-Allyl-5-(N-allyl-N-carbobenzyloxy)aminoindazole (XXVI')
Allyl bromide (1.70 ml) is added to a mixture of
1-carbo-t-butyloxy-5-(N-carbobenzyloxy)aminoindazole (XXV, EXAMPLE
59, 5.805 g) and sodium hydride/mineral oil (50% by wight, 1.000 g,
15.8 mmol sodium hydride) in freshly distilled THF (80 ml). The
mixture is refluxed for 20 hr under nitrogen, then poured into
water (100 ml). The aqueous mixture is extracted with ethyl acetate
(3.times.100 ml). The combined organic layers are washed with
saline, dried over magnesium sulfate, and concentrated to an oil.
The oil is passed over a silica gel column (26.times.4.5 cm,
40-63.mu.), eluting with ethyl acetate/hexane (1/4 2 1, 1/1 1 1)
and ethyl acetate (300 ml) collecting 47 ml fractions. The
appropriate fractions are pooled and concentrated give
1-carbo-t-butyloxy-5-(N-allyl-N-carbobenzyloxy)aminoindazole (XXVI)
NMR (CDCl.sub.3, 300 MHz) 8.14, 7.59, 7.34, 5.93, 5.16, 5.11, 4.32
and 1.71 .delta.; CMR (CDCl.sub.3, 75.47 MHz) 27.99, 53.53, 57.32,
84.91, 114.51, 114.75, 126.00, 127.56, 127.85, 128.30, 132.67,
133.294, 137.93, 139.24, 148.87 and 155.24 .delta.; MS (m/e) 407,
307, 172, 91, 57 and 40. Later eluting fractions are pooled and
concentrated give 1-allyl-5-(N-allyl-N-carbobenzyloxy)
aminoindazole (XXVI') NMR (CDCl.sub.3, 300 MHz) 7.91, 7.68, 7.47,
7.28, 7.14, 6.18-6.05, 6.00-5.87, 5.37-5.29, 5.16-5.11, 5.04-5.01
and 4.29 .delta.; CMR (CDCl.sub.3, 75.47 MHz, major peaks) 53.59,
55.91, 67.08, 117.20, 117.56, 117.93, 119.28, 121.48, 123.12,
126.72, 127.43, 127.70, 128.25, 132.07, 133.65, 136.55, 147.39 and
155.46 .delta..
EXAMPLE 61
(.+-.)-3-[5'-(1-Carbo-t-butyloxyindazolyl)]-5-(iodomethyl)oxazolidin-2-one
(XXVII)
(.+-.)-3-[5'-(1-Allylindazolyl)]-5-(iodomethyl)oxazolidin-2-one
(XXVII')
Iodine (4.699 g) is added to 3.580 g of a mixture of
1-carbo-t-butyloxy-5-(N-allyl-N-carbobenzyloxy)aminoindazole (XXVI,
EXAMPLE 60) and 1-allyl-5-(N-allyl-N-carbobenzyloxy)aminoindazole
(XXVI', EXAMPLE 60) in chloroform (95 ml). The mixture is stirred
under nitrogen for 1.5 hr then poured into aqueous sodium
thiosulfate (10%, 100 ml). The layers are separated, and the
organic layer is washed with additional aqueous sodium thiosulfate
(10%, 2.times.50 ml). The aqueous layers are combined and extracted
with ethyl acetate (3.times., 200 ml total). The organic layers are
combined, dried over magnesium sulfate and concentrated to give an
oil. The oil is adsorbed onto silica gel (40-63.mu.) then placed on
a silica gel column (35.times.5.5 cm, 40-63.mu.) eluting with ethyl
acetate/:hexane (1/3, 500 ml; 1/1, 2 1) and methanol/ethyl acetate
(1/9, 2 1) collecting 41 ml fractions. The appropriate fractions
are poled and concentrated give (.+-.)-3-[5'-(1-allylindazolyl)]-
5-(iodomethyl)oxazolidin-2-one (XXVII'), NMR (CDCl.sub.3, 300 MHz)
7.98, 7.72, 7.68, 7.4, 6.01, 5.22, 5.14, 5.08, 5.02, 5.00, 4.73,
4.23, 3.84, 3.47 and 3.39 .delta.; CMR (CDCl.sub.3, 75.47 MHz)
6.29, 51.76, 51.87, 71.09, 109.86, 110.86, 117.76, 119.68, 123.97,
131.30, 132.45, 132.98, 136.90 and 154.4; IR (Neat) 1746, 1510,
1417, 1226 and 1112 cm.sup.-1 ; MS (m/e) 383, 255, 212, 184, 170,
157 and 40.
Later eluting fractions are pooled and concentrated give
(.+-.)-3-[5'-(1-carbo-t-butyloxyindazolyl)]-5-(iodomethyl)oxazolidin-2-one
(XXVII) which is recrystallized from acetone, NMR (CDCl.sub.3, 300
MHz) 8.18, 7.87, 7.78, 4.78, 4.27, 3.88, 3.51, 3.41 and 1.73
.delta.; CMR (CDCl.sub.3, 75.47 MHz) 5.95, 28.04, 51.42, 71.14,
85.04, 110.16, 115.01, 120.51, 125.98, 133.85, 136.8, 139.22, 149.1
and 154.5 .delta.; IR (mineral oil mull) 1745, 1390 and 1155
cm.sup.-1 ; MS (m/e) 443, 343, 172, 144, 117, 57 and 40.
EXAMPLE 62
(.+-.)-3-(4'-Indazolyl)-5-(azidomethyl)oxazolidin-2-one
(XXVIII)
(.+-.)-3-[5'-(1-Allylindazolyl)]-5-(azidomethyl)oxazolidin-2-one
(XXVIII')
A mixture (2.515 g) of
(.+-.)-3-[5'-(1-carbo-t-butyloxyindazolyl)]-5-(iodomethyl)oxazolidin-2-one
(XXVII, EXAMPLE 61) and
(.+-.)-3-[5'-(1-allylindazolyl)]-5-(iodomethyl)oxazolidin-2-one
(XXVII', EXAMPLE 61) is stirred with sodium azide (2.575 g) in
refluxing water/acetone (1/2, 150 ml) under nitrogen for 25 hr. The
mixture is then poured into ethyl acetate (100 ml). The layers are
separated. The aqueous phase is extracted with ethyl acetate
(3.times.25 ml). The combined organic layers are dried over
magnesium sulfate and concentrated to an oil. A sample of the oil
is purified by preparative TLC. From the purification
(.+-.)-3-(5'-indazolyl)-5-(azidomethyl)oxazolidin-2-one (XXVIII),
NMR (CDCl.sub.3 ca. 0.5% DMF-d.sub.7, 300 MHz) 9.5-8.5, 8.02, 7.69,
7.55, 4.84, 4.20, 3.92, 3.74 and 3.62 .delta.; CMR (CDCl.sub.3, ca.
0.5% DMF-d.sub.7, 75.47 MHz, 300 MHz) 48.24, 52.96, 70.66, 110.38,
110.75, 122.8, 131,5, 133.9, 137.8 and 154.9 .delta.; IR (neat)
2108, 1741, 1511, 1420 and 1277 and
(.+-.)-3-[5'-(1-allylindazolyl)]-5-(azidomethyl)oxazolidin-2-one
(XXVIII') NMR (CDCl.sub.3, 300 MHz) 7.99, 7.74, 7.68, 7.42, 6.02,
5.23, 5.12, 5.02, 4.82, 4.16, 3.94, 3.73 and 3.62 .delta.; CMR
(CDCl.sub.3, 75.47 MHz) 48.33, 51.78, 52.98, 70.54, 109.88, 110.79,
117.76, 119.65, 124.1, 131.7, 132.42, 132.98, 137.3 and 154.6
.delta.; IR (neat) 2105, 1746, 1510, 1418 and 1224 cm.sup.-1.
EXAMPLE 63
(.+-.)-3-(5'-Indazolyl)-5-(aminomethyl)oxazolidin-2-one (XXIX)
(.+-.)-3-[5'-(1-n-Propylindazolyl)]-5-(aminomethyl)oxazolidin-2-one
(XXIX')
Palladium on carbon (10%, 540 mg) is added to a combined mixture
(2.000 g) of (.+-.)-3-(5'-indazolyl)
-5-(azidomethyl)oxazolidin-2-one (XXVIII, EXAMPLE 62) and
(.+-.)-3-[5'-(1-allylindazolyl)]-5-(azidomethyl)oxazolidin-2-one
(XXVIII', EXAMPLE 62) in methanol/ethyl acetate (105, 110 ml). The
mixture is stirred under 1 atm of hydrogen (balloon) overnight. The
mixture is then filtered over diatomaceous earth and the filtrate
concentrated to a tar. The crude material is dissolved and is
passed over a silica gel column (23.times.4 cm, 40-63.mu.) eluting
with methanol/chloroform (1/9, 600 ml, 1/4, 1.51) collecting 46 ml
fractions. The appropriate fractions are pooled and concentrated
give (.+-.)-3-[5'-(1-n-propylindazolyl)]-5-(aminomethyl)
oxazolidin-2-one (XXIX'), NMR (MeOD, 300 MHz) 7.96, 7.73, 7.52,
4.71, 4.31, 4.14, 3.87, 2.98, 1.87 and 0.84 .delta.; CMR (MeOD,
75.47 MHz) 11.64, 24.35, 45.61, 50.12, 51.37, 75.62, 110.96,
112.42, 121.60, 124.95, 133.32, 133.81, 138.50 and 157.50 .delta.;
IR (neat) 1741, 1510, 1418, 1225 and 1113 cm.sup.-1. Later eluting
fractions are pooled and concentrated give
(.+-.)-3-(5'-indazolyl)-5-(aminomethyl)oxazolidin-2-one (XXIX), NMR
(MeOD, 300 MHz) 8.02, 7.77, 7.70, 7.55, 4.78, 4.17, 3.89 and 3.05
.delta.; CMR (MeOD, 75.47 MHz) 45.43, 50.35, 75.35, 111.76, 112.52,
122.02, 124.19, 133.16, 134.99, 139.20 and 157.60 .delta.; IR
(neat) 3800-3000 very broad, 1735, 1511 and 1423 cm.sup.-1.
EXAMPLE 64
(.+-.)-3-(5'-Indazolyl)-5-(acetamidomethyl)oxazolidin-2one
(XXXI)
Acetic anhydride (0.5 ml) is added to
(.+-.)-3-(5'-indazolyl)-5-(aminomethyl)oxazolidin-2-one (XXIX,
EXAMPLE 63, 152 mg) in pyridine (1,5 ml) at 0.degree.. The mixture
is stirred for two hr while allowing it to warm to
20.degree.-25.degree.. The mixture is then concentrated under
reduced pressure to a solid. The solid is purified on a silica
preparative plate (1000.mu.) developing with methanol/chloroform
(1/10) to give
(.+-.)-3-(5'-(1-acetylindazolyl))-5-acetamidomethyl-2-oxazolidin-2-one
(XXX), NMR (CH.sub.3 OD, 300 MHz) 8.03, 7.76, 7.70, 7.54, 4.79,
4.20, 3.89, 3.58 and 1.98 .delta.; CMR (CH.sub.3 OD, 75.47 MHz)
22.49, 43.23, 50.28, 73.58, 111.70, 112.43, 124,.3, 133.5, 135.2,
139.6, 157.9 and 174.5 .delta. and
(.+-.)-3-(5'-indazolyl)-5-acetamidomethyl-2-oxazolidin-2-one
(XXXI), NMR (CDCl.sub.3, 300 MHz) 8.37, 8.08. 7.85, 7.69, 6.61,
4.83, 4.14, 3.91, 3.70, 2.78 and 2.04 .delta.; CMR (CDCl.sub.3,
75.47 MHz) 22.73, 22.93, 41.77, 47.94, 71.95, 109.92, 115.82,
120.64, 126.51, 134.55, 135.6, 139.37, 154.5, 170.75 and 171.16
.delta..
EXAMPLE 65
(.+-.)-3-[5'-(1-Ethylindazolyl)]-5-(acetamidomethyl)oxazolidin-2
-one (XXXII)
Starting with
(.+-.)-3-(5'-indazolyl)-5-(acetamidomethyl)oxazolidin-2-one (XXXI,
EXAMPLE 64) in methanol and acetaldehyde (2 equivalents), the
mixture is treated with glacial acetic acid to bring the pH to 5.
After stirring the mixture for 1-2 hr, 1 equivalent of sodium
cyanoborohydride is added and the mixture is stirred for 24 hr at
20.degree.-25.degree.. The mixture is then concentrated under
reduced pressure. Water is added, and the pH is adjusted to 7-8
with 1N aqueous potassium hydroxide, then extracted with chloroform
(3.times.). The organic extracts are combined, dried over magnesium
sulfate and concentrated under reduced pressure to give the title
compound. It can be purified by recrystallization or column
chromatography on silica gel if desired.
EXAMPLE 66
(.+-.)-3-[5'-(1-n-Propylindazolyl)]-5-(acetamidomethyl)oxazolidin-2-one
(XXX')
Acetic anhydride (0.5 ml) is added to
(.+-.)-3-[5'-(1-n-propylindazolyl)]-5-(aminomethyl)
oxazolidin-2-one (XXIX', EXAMPLE 63, 126 mg) in pyridine (1.5 ml)
at 0.degree.. The mixture is stirred for two hr while allowing it
to warm to 20.degree.-25.degree.. The mixture is then concentrated
under reduced pressure to a solid. The solid is purified on a
silica preparative plate (1000.mu.) developing with
methanol/chloroform (1/10) to give the title compound, NMR
(CDCl.sub.3, 300 MHz) 7.95, 7.66, 7.39, 6.91, 4.80, 4.33, 4.10,
3.89, 3.66, 2.02, 1.93 and 0.90 .delta.; CMR (CDCl.sub.3, 75.47
MHz); .delta. 11.22, 22.84, 23.09, 41.81, 48.53, 50.53, 71.98,
109.51, 110.98, 119.53, 123.62, 131.11, 132.47, 136.92, 155.19 and
171.27 .delta..
EXAMPLE 67
1-Ethyl-2-methyl-(N-carbobenzyloxy)-5-aminobenzimidazole
(XXXVI)
An aqueous sodium bicarbonate solution (0.137 g/ml) is very slowly
added to a solution of 1-ethyl-2-methyl-5-aminobenzimidazole
hydrochloride (XXXV, 9.715 g) in water (50 ml). A precipitate
formes from the effervescent mixture. The precipitate is dissolved
by adding acetone (50 ml), and remained in solution after adding
another 70 ml of the sodium bicarbonate solution (13.667 g sodium
bicarbonate total). After the mixture is cooled to 0.degree. under
nitrogen, benzylchloroformate (5.7 ml) is added slowly over two
min. The mixture is then slowly warmed to 20.degree.-25.degree..
More acetone is added (100 ml) to dissolve a precipitate that is
formed. After 22 hrs benzylchloroformate (150 .mu.l) is added. Then
after 2.5 hrs the mixture is poured into ethylacetate. The layers
are separated, and the aqueous phase is extracted with ethyl
acetate, 4.times.. The combined organic layers are washed with
aqueous sodium bisulfate (10%, 2.times.), which removed the color.
The desired product is in the aqueous sodium bisulfate washings.
These aqueous layers are made alkaline (pH.about.14) with sodium
hydroxide (5N). A solid is obtained after filtering the alkaline
mixture. The solid is then triturated in boiling acetone, 4.times.,
filtering after each trituration. The filtrates are combined and
concentrated to give the title compound, mp 145-150; NMR
(CDCl.sub.3, 300 MHz) 7.58, 7.4-7.26, 7.18, 5.20, 4.08, 2.54, 1.35
.delta.; CMR (CDCl.sub.3, 75.47 MHz) 13.56, 14.78, 33.42, 66.67,
108.84, 109,6, 115.2, 128.06, 128.11, 128.41, 131.7, 132.8, 136.24,
142.66, 151.68 and 154.1 .delta.; IR (mineral oil mull) 1723, 1569,
1496, 1240 and 1060 cm.sup.-1 ; MS (m/e) 309, 174 and 91; exact
mass calcd for C.sub.18 H.sub.19 N.sub.5 O.sub.2 =309.1477, found
309.1495.
EXAMPLE 68
1-Ethyl-2-methyl-(N-allyl-N-carbobenzyloxy)-5-aminobenzimidazole
(XXXVII)
Allyl bromide (2.5 ml) is added to a mixture of
1-ethyl-2-methyl-(N-carbobenzyloxy)-5-aminobenzimidazole (XXXVI,
EXAMPLE 67, 6.780 g) and sodium hydride/mineral oil (50% by weight,
1.374 g, 28.6 mmol NaH) in freshly distilled THF (150 ml). The
mixture is refluxed under nitrogen. After 21 hrs, the mixture is
poured into water (100 ml) and extracted with ethyl acetate
(3.times.200 ml). The organic layers are combined, dried over
magnesium sulfate and concentrated under reduced pressure to give
an oil. A portion of this oil (509 mg) is passed over a silica
column (34.times.2.5 cm, 40-63.mu.) eluting with ethyl
acetate/hexane (70/30, 700 ml) and 1500 ml ethyl acetate. The
appropriate fractions are pooled and concentrated to give the title
compound as an oil, NMR (CDCl.sub.3, 300 MHz) 7.53, 7.23-7.09,
5.91, 5.10, 4.30, 3.97, 2.49, and 1.28 .delta.; CMR (CDCl.sub.3,
75.47 MHz) 13.50, 14.67, 38.30, 53.91, 66.90, 108.71, 117.14,
117.46, 121.30, 127.30, 127.54, 128.15, 133.25, 133.58, 136.5,
136.65, 142.65, 151.95 and 155.50 .delta.; IR (Mineral oil mull)
1698, 1402, 1409 and 1245 cm.sup.-1 ; MS (m/e) 349, 214, 186, 184,
159, 92 and 91; exact mass calcd for C.sub.21 H.sub.23 N.sub.3
O.sub.2 =349.1790, found 349.1786.
EXAMPLE 69
(.+-.)-3-(5'-1-ethyl-2-methylbenzimidazolyl)-5-(iodomethyl)oxazolidin-2-one
(XXXVIII)
Iodine (25.372 g) is added to a mixture of
1-ethyl-2-methyl-(N-allyl-N-carbobenzyloxy)-5-aminobenzimidazole
(XXXVII, EXAMPLE 68, 7.790 g) in chloroform (200 ml). After 25 min
the mixture is poured into aqueous sodium thiosulfate (10%, 100 ml)
and the layers are separated. The organic layer is washed again
with sodium thiosulfate (10%, 3.times., 250 ml total). The organic
phases are combined and dried over magnesium sulfate and
concentrated to give a solid. The solid is dissolved in methylene
chloride and passed over a silica column (36.times.5.5 cm,
40-63.mu.). The column is eluted with a methylene
chloride.fwdarw.methanol/methylene chloride (50/50) gradient. The
appropriate fractions are pooled and concentrated to provide crude
product. The crude desired product is dissolved in chloroform (3
ml) and passed over a silica gel column (27.times.4.5 cm,
40-63.mu.). The column is eluted with ethyl acetate (2 l),
methanol/ethyl acetate (10/90, 1 l) and methanol/ethyl acetate
(20%, 1 l). The appropriate fractions are pooled and concentrated
to give the title compound, mp=143.degree.-144.degree.; NMR
(CDCl.sub.3, 300 MHz) 7.65, 7.55, 7.28, 4.72, 4.23, 4.15, 3.83,
3.50-3.37, 2.60 and 1.40 .delta.; CMR (CDCl.sub.3, 75.47 MHz) 6.37,
13.64, 14.81, 38.60, 51.99, 71.04, 109.24, 109.55, 115.06, 131.89,
132.54, 142.41, 152.11 and 154.44 .delta.; IR (mineral oil mull)
1737, 1499 and 1411 cm.sup.-1 ; MS (m/e) 385, 257, 214, 186 and
159; exact mass calcd for C.sub.14 H.sub.16 IN.sub.3 O.sub.2
=385.0289; found 385.0300.
EXAMPLE 70
(.+-.)-3-(5'-1-Ethyl-2-methylbenzimidazolyl)-5-(azidomethyl)oxazolidin-2-on
e (XXXIX)
A mixture of
(.+-.)-3-(5'-1-ethyl-2-methylbenzimidazolyl)-5-(iodomethyl)oxazolidin-2-on
e (XXXVIII, EXAMPLE 69, 0.531 g) and sodium azide (0.618 g) are
stirred in acetone/water (2/1, 30 ml) at reflux under a nitrogen
overnight. After this time the mixture is poured into ethyl acetate
and the layers are separated. The aqueous layer is then extracted
with ethyl acetate (2.times.). All organic layers are combined,
dried over magnesium sulfate and concentrated under reduced
pressure to give an oil. A small amount of the crude product (oil)
is purified on a silica preparative plate (20 cm.times.20 cm,
1000.mu.). The plate is eluted in methanol/ethyl acetate (10/90,
5.times.) to give the title compound as an oil; NMR (CDCl.sub.3,
300 MHz) 7.70, 7.53, 7.30, 4.80, 4.15, 3.89, 3.70, 3.60, 2.61 and
3.40 .delta.; CMR (CDCl.sub.3, 75.47 MHz) 13.62, 14.78, 38.62,
48.42, 53.05, 70.60, 109.29, 114.99, 132.1, 132.72, 142.3, 152.8
and 154.9 .delta.; MS (m/e) 300, 272, 227, 212, 200, 186, 172, 160,
159, 145, 131, 117, 104, 90 and 77; exact mass calcd for C.sub.14
H.sub.16 N.sub.6 O.sub.2 =300.1335, found: 300.1333.
EXAMPLE 71
(.+-.)-3-(5'-1-Ethyl-2-methylbenzimidazolyl)-5-(aminomethyl)oxazolidin-2-on
e (XL)
A mixture of
(.+-.)-3-(5'-1-ethyl-2-methylbenzimidazolyl)-5-(azidomethyl)oxazolidin-2-o
ne (XXXIX, EXAMPLE 70, 0.190 g) and palladium on carbon (10%, 0.065
g) is stirred in ethyl acetate (70 ml) for 15.5 hrs under 1 atm
(balloon) hydrogen. The mixture is then filtered and the filtrate
concentrated to give the crude product as a solid in an oil. The
crude sample is placed on a silica gel column (5 cm.times.0.5 cm,
40-63.mu.) and eluted with ethyl acetate followed by methanol/ethyl
acetate mixtures (1/9 10 ml, 1/3 20 ml, 1/1 20 ml. The 1/3 and 1/1
methanol/ethyl acetate fractions are combined and concentrated to
give the title compound as a foamy solid. NMR (CDCl.sub.3, 300 MHz)
7.64, 7.55, 7.24, 4.70, 4.10, 3.87, 3.12, 3.01, 2.57 and 1.36
.delta.; CMR (CDCl.sub.3, 75.47 MHz) 13.60, 14.77, 38.46, 44.80,
48.61, 73.57, 109.06, 109.17, 114.63, 131.64, 132.86, 142.52,
152.02 and 155.09 .delta..
EXAMPLE 72
(.+-.)-3-(5'-1-Ethyl-2-methylbenzimidazolyl)-5-(acetamidomethyl)oxazolidin-
2-one (XLI/XLIII)
A mixture of
(.+-.)-3-(5'-1-Ethyl-2-methylbenzimidazolyl)-5-(aminomethyl)oxazolidin-2-o
ne (XL, EXAMPLE 71, 0.100 g) in pyridine (2 ml) and acetic
anhydride (1 ml) is stirred under nitrogen for 2 hrs. The mixture
is then concentrated under reduced pressure to give the title
compound, no further purification is necessary by analysis, mp
217.degree.-218.degree., NMR (CDCl.sub.3 /DMF-d.sub.7, 300 MHz)
7.74, 7.52, 4.80, 4.27, 3.93, 3.58, 2.61 and 1.38 .delta.; CMR
(DMF-d.sub.7, 75.47 MHz) 13.06, 14.67, 22.2, 38.65, 42.2, 72.01,
101.7, 109.34, 109.96, 114.57, 132.5, 134.2, 143.3, 153.5, 155.7
and 171.7 .delta..
EXAMPLE 73
(.+-.)-3-(5'-1-Propylbenzimidazolyl)-5-(aminomethyl)oxazolidin-2-one
(XL)
Following the general procedure of EXAMPLES 67-71 and making
non-critical variations but starting with
1-propyl-5-aminobenzimidazole hydrochloride (XXXV), the title
compound is obtained.
EXAMPLE 74
(.+-.)-3-(5'-1-Carbo-t-butyloxy-2-methylbenzimidazolyl)-5-(aminomethyl)oxaz
olidin-2-one (XL)
Following the general procedure of EXAMPLES 57, 58 and 67-71 and
making non-critical variations but starting with
2-methyl-5-nitrobenzimidazole (XXXIII), the title compound is
obtained.
EXAMPLE 75
(.+-.)-3-(5'-1-Carbo-t-butyloxybenzimidazolyl)-5-(aminomethyl)oxazolidin-2-
one (XL)
Following the general procedure of EXAMPLE 74 and making
non-critical variations but starting with 5-nitrobenzimidazole
(XXXIII), the title compound is obtained.
EXAMPLE 76
3-(5'-Indazolyl)-5.beta.-(aminomethyl)oxazolidin-2-one (XXIX)
(.+-.)-3-(5'-Indazolyl)-5-(aminomethyl)oxazolidin-2-one (XXIX,
EXAMPLE 63) is stirred with (+) or (-) tartaric acid in methylene
chloride and then permitted to stand while the product crystallizes
out. The crystalline product is obtained by filtration and treated
with triethylamine or sodium bicarbonate to obtain the free amine
which is obtained by extraction with methylene chloride. The
methylene chloride extract is concentrated to give the title
compound.
EXAMPLES 77-81
Following the general procedure of EXAMPLE 76 and making
non-critical variations but starting with the racemic mixtures of
EXAMPLES 63, 71, 73, 74 and 75, the compounds of EXAMPLES 77-81 are
obtained:
______________________________________ 77
3-[5'-(1-n-Propylindazolyl)]-5.beta.-(aminomethyl)oxazolidin- 2-one
(XXIX'), 78
3-(5'-1-Ethyl-2-methylbenzimidazolyl)-5.beta.-(aminomethyl)
oxazolidin-2-one (XL), 79
3-(5'-1-Propylbenzimidazolyl)-5.beta.-(aminomethyl)oxazolidin-
2-one (XL), 80
3-(5'-1-Carbo-t-butyloxy-2-methylbenzimidazolyl)5.beta.-
(aminomethyl)-oxazolidin-2-one (XL) and 81
3-(5'-1-Carbo-t-butyloxybenzimidazolyl)-5.beta.-(aminomethyl)
oxazolidin-2-one (XL). ______________________________________
EXAMPLE 82
3-[5'-(1-Acetylindazolyl)]-5.beta.-(acetamidomethyl)oxazolidin-2-one
(XXX)
3-(5'-Indazolyl)-5.beta.-(acetamidomethyl)oxazolidin-2-one
(XXXI)
Following the general procedure of EXAMPLE 64 and making
non-critical variations but starting with the optically active
3-(5'-indazolyl)-5.beta.-(aminomethyl)oxazolidin-2-one (XXIX,
EXAMPLE 76) the title compounds are obtained.
EXAMPLE 83
3-[5'-(1-Ethylindazolyl)]-5.beta.-(acetamidomethyl)oxazolidin-2-one
(XXXIII)
Following the general procedure of EXAMPLE 65 and making
non-critical variations but starting with the optically active
3-(5'-indazolyl)-5.beta.-(acetamidomethyl)oxazolidin-2-one (XXXI,
EXAMPLE 82) the title compound is obtained.
EXAMPLE 84
3-[5'-(1-n-Propylindazolyl)]-5.beta.-(acetamidomethyl)oxazolidin-2-one
(XXX')
Following the general procedure of EXAMPLE 66 and making
non-critical variations but starting with the optically active
3-[5'-(1-n-propylindazolyl)]-5.beta.-(aminomethyl)oxazolidin-2-one
(XXIX', EXAMPLE 77) the title compound is obtained.
EXAMPLE 85
3-(5'-1-Ethyl-2-methylbenzimidazolyl)-5.beta.-(acetamidomethyl)oxazolidin-2
-one (XLI/XLIII)
Following the general procedure of EXAMPLE 72 and making
non-critical variations but starting with the optically active
3-(5'-1-ethyl-2-methylbenzimidazolyl)-5.beta.-(aminomethyl)
oxazolidin-2-one (XL, EXAMPLE 78) the title compound is
obtained.
EXAMPLE 86
3-(5'-1-Propylbenzimidazolyl)-5.beta.-(acetamidomethyl)oxazolidin-2-one
(XLI/XLIII)
Following the general procedure of EXAMPLE 72 and making
non-critical variations but starting with the optically active
3-(5'-1-propylbenzimidazolyl)-5.beta.-(aminomethyl)oxazolidin-2-one
(XL, EXAMPLE 79) the title compound is obtained.
EXAMPLE 87
3-(5'-1-Carbo-t-butyloxy-2-methylbenzimidazolyl)-5.beta.-(acetamidomethyl)o
xazolidin-2-one (XLI)
Following the general procedure of EXAMPLE 72 and making
non-critical variations but starting with the optically active
3-(5'-1-carbo-t-butyloxy-2-methylbenzimidazolyl)-5.beta.-(-aminomethyl)oxa
zolidin-2-one (XL, EXAMPLE 80), the title compound is obtained.
EXAMPLE 88
3-(5'-2-Methylbenzimidazolyl)-5.beta.-(acetamidomethyl)oxazolidin-2-one
(XLII)
3-(5'-1-Carbo-t-butyloxy-2-methylbenzimidazolyl)-5.beta.-(acetamidomethyl)o
xazolidin-2-one (XLI, EXAMPLE 87) is contacted with trifluoroacetic
acid as is known to those skilled in the art to remove the
carbo-t-butyloxy protecting group. Upon workup the title compound
is obtained.
EXAMPLE 89
3-(5'-1-Acetyl-2methylbenzimidazolyl)-5.beta.-(acetamidomethyl)oxazolidin-2
-one (XLIII)
Following the general procedure of EXAMPLE 64 and making
non-critical variations but starting with
3-(5'-2-methylbenzimidazolyl)-5.beta.-(acetamidomethyl)oxazolidin-2one
(XLII, EXAMPLE 88) the title compound is obtained.
EXAMPLE 90
3-5'-1-Formylbenzimidazolyl)-5.beta.-(acetamidomethyl)oxazolidin-2-one
(XLIII)
Following the general procedure of Examples 87, 88 and 89 but
starting with
3-(5'-1-carbo-t-butyloxybenzimidazolyl)-5.beta.-(aminomethyl)oxazolidin-2-
one (XL, EXAMPLE 81) and using formic acid and acetic anhydride as
the acylating agent, the title compound is obtained.
EXAMPLES 91-94
Following the general procedure of EXAMPLE 76 and making
non-critical variations but starting with the racemic mixtures of
Examples 7, 15, 31 and 45 the compounds of EXAMPLE 91-94 are
obtained:
______________________________________ 91
3-(5'-1-Acetylindolinyl)-5.beta.-(aminomethyl) oxazolidin-2-one
(VIII), 92
3-(5'-1-Carbo-t-butyloxyindolinyl)-5.beta.-(aminomethyl)oxazolidin-
2-one (VIII), 93
3-(6'-1-Carbo-t-butyloxyindolinyl)-5.beta.-(aminomethyl)oxazolidin-
2-one (VIII), 94
3-(5'-indanyl)-5.beta.-(aminomethyl)oxazolidin-2-one
______________________________________ (XXA).
EXAMPLE 95
3-(5'-1-Acetylindolinyl)-5.beta.-(acetamidomethyl)oxazolidin-2-one
(IX)
Following the general procedure of EXAMPLE 8 and making
non-critical variations but starting with
3-(5'-1-acetylindolinyl)-5.beta.-(aminomethyl)oxazolidin-2-one
(VIII, EXAMPLE 91), the title compound is obtained.
EXAMPLE 96
3-(5'-1-Carbo-t-butyloxyindolinyl)-5.beta.-(acetamidomethyl)oxazolidin-2-on
e (IX)
Following the general procedure of EXAMPLE 16 and making
non-critical variations but starting with
3-(5'-1-carbo-t-butyloxyindolinyl)-5.beta.-(aminomethyl)-2-one
(VIII, EXAMPLE 92), the title compound is obtained.
EXAMPLE 97
3-(5'-Indolinyl)-5.beta.-(acetamidomethyl)oxazolidin-2-one (X)
Following the general procedure of EXAMPLE 17 and making
non-critical variations but starting with
3-(5'-1-carbo-t-butyloxyindolinyl)-5.beta.-(acetamidomethyl)oxazolidin-2-o
ne (IX, EXAMPLE 96), the title compound is obtained.
EXAMPLE 98
3-5'-Isobutyrlindolinyl)-5.beta.-(acetamidomethyl)oxazolidin-2-one
(XI)
Following the general procedure of EXAMPLE 18 and making
non-critical variations but starting with
3-(5'-indolinyl)-5.beta.-(acetamidomethyl)oxazolidin-2-one (X,
EXAMPLE 97), the title compound is obtained.
EXAMPLE 99
3(6'-1-Carbo-t-butyloxyindolinyl)-5.beta.-(acetamidomethyl)oxazolidin-2-one
(IX)
Following the general procedure of EXAMPLE 32 making non-critical
variations but starting with
3-(6'-1-Carbo-t-butyloxyindolinyl)-5.beta.-(aminomethyl)oxazolidin-2-one
(VIII, Example 93), the title compound is obtained.
EXAMPLE 100
3-(6'-Indolinyl)-5.beta.-(acetamidomethyl)oxazolidin-2-one (X)
Following the general procedure of Example 33 and making
non-critical variations but starting with
3-(6'-1-Carbo-t-butyloxyindolinyl)-5.beta.-(acetamidomethyl)oxazolidin-2-o
ne (IX, EXAMPLE 99), the title compound is obtained.
EXAMPLE 101
3-(5'-1-Allylindolinyl-5.beta.-(acetamidomethyl)oxazolidin-2-one
(XL)
Following the general procedure of EXAMPLE 18 and making
non-critical variations but starting with
3-(5'-indolinyl)-5.beta.-(acetamidomethyl)oxazolidin-2-one (X,
EXAMPLE 97) and using allyl bromide, the title compound is
obtained.
EXAMPLE 102
(.+-.)-3-(6'-1-Allylindolinyl)-5.beta.-(acetamidomethyl)oxazolidin-2-one
(XI)
Following the general procedure of EXAMPLE 18 and making
non-critical variations but starting with
3-(6'-indolinyl)-5.beta.-(acetamidomethyl)oxazolidin-2-one (X,
EXAMPLE 100) and using allyl bromide, the title compound is
obtained.
EXAMPLES 103-107
Following the general procedure of EXAMPLES 46, 47, 48, 49 and 51
and making non-critical variations but starting with
3-(5'-indanyl)-5.beta.-(aminomethyl)oxazolidin-2-one (XXA, EXAMPLE
94), the compounds of EXAMPLES 103-107 are obtained:
______________________________________ 103
3-(5'-Indanyl)-5.beta.-(acetamidomethyl)oxazolidin-2-one (XXIA),
104 3-(5'-Indanyl)-5.beta.-(butyramidomethyl)oxazolidin-2-one
(XXIA), 105 3-(5'-Indanyl)-5.beta.-(cyclopropylcarboxamidomethyl)
oxazolidin-2-one (XXIA), 106
3-(5'-Indanyl)-5.beta.-(formylamidomethyl)oxazolidin-2-one (XXIA),
107 3-(5'-Indanyl)-5.beta.-(methoxycarboxamidomethyl)oxazolidin-
2-one (XXIA). ______________________________________
EXAMPLE 108
3-(1'-Oxo-5'-indanyl)-5.beta.-(acetamidomethyl)oxazolidin-2-one
(XXIB)
Following the general procedure of EXAMPLE 52 and making
non-critical variations but starting with
3-(5'-indanyl)-5.beta.-(acetamidomethyl)oxazolidin-2-one (XXIA,
EXAMPLE 103), the title compound is obtained.
EXAMPLE 109
3-(1-Oximino-5'-indanyl-5.beta.-(acetamidomethyl)oxazolidinone
(XXIE)
Following the general procedure of EXAMPLE 53 and making
non-critical variations but starting with
3-(1'-oxo5'-indanyl)-5.beta.-(acetamidomethyl)oxazolidin-2-one
(XXIB, EXAMPLE 108), the title compound is obtained.
EXAMPLE 110
3-(1'-Hydroxy-5'-indanyl)-5.beta.-(acetamidomethyl)oxazolidin-2-one
(XXIC)
Following the general procedure of EXAMPLE 54 and making
non-critical variations but starting with
3-(1'-oxo-5'-indanyl-5.beta.-(acetamidomethyl)oxazolidin-2-one
(XXIB, EXAMPLE 108), the title compound is obtained.
EXAMPLE 111
3-(6'-Tetralinyl)-5.beta.-(acetamidomethyl)oxazolidin-2-one
(XXIA)
Following the general procedure of EXAMPLES 41-44 and 94, and
making non-critical variation but starting with 6-aminotetralin,
the title compound is obtained.
EXAMPLE 112
3(1'-Oxo-6'-tetralinyl)-5.beta.-(acetamidomethyl)oxazolidin-2one
(XXIB)
Following the general procedure of EXAMPLE 52 and making
non-critical variations, but starting with
3-(6'-tetralinyl)-5.beta.-(acetamidomethyl)oxazolidin-2-one (XXIA,
EXAMPLE 111), the title compound is obtained.
EXAMPLES 113-118
Following the general procedure of EXAMPLES 19-24 and making
non-critical variations but starting with
3-(5'-indolinyl)-5.beta.-(acetamidomethyl)oxazolidin-2-one (X,
EXAMPLE 97), the compounds of EXAMPLES 113-118 are obtained:
______________________________________ 113
3-(5'-1-Propanoylindolinyl)-5.beta.-(acetamidomethyl)
oxazolidin-2-one (XI), 114
3-(5'-1-Cyclopentylcarbonylindolinyl)-5.beta.-(acetamido methyl)
oxazolidin-2-one (XI), 115
3-(5'-1-Formylindolinyl)-5.beta.-(acetamidomethyl)oxazolidin- 2-one
(XI), 116 3-(5'-1-Chloroacetylindolinyl)-5.beta.-(acetamidomethyl)
oxazolidin-2-one (XI), 117
3-(5'-1-Dichloroacetylindolinyl)-5.beta.-(acetamidomethyl)
oxazolidin-2-one (XI) and 118
3-(5'-1-Phenylacetylindolinyl)-5.beta.-(acetamidomethyl)
oxazolidin-2-one (XI) ______________________________________
EXAMPLES 119-128
Following the general procedure of
1. EXAMPLES 1-7 for production of the protected aminomethyl
(VIII),
2. EXAMPLES 16-18 for production of the optically active (XI),
3. For the cases with hydroxyacetyl and propyl, in addition, follow
the procedures of EXAMPLES 2 or 10 (reduction of nitro to amino is
the same conditions as for reduction of allyl to propyl or cleavage
of a benzyl group) and making non-critical variations but starting
with appropriately substituted nitroindoline (I), the compounds of
EXAMPLES 119-128 are obtained:
______________________________________ 119
(.+-.)-3-(5'-1-Benzoylindolinyl)-5.beta.-(acetamidomethyl)
oxazolidin-2-one (XI), mp 215-216.degree.; 120
(.+-.)-3-(5'-1-Methylsulfonylindolinyl)-5.beta.-(acetamidomethyl)
oxazolidin-2-one (XI), mp 177-178.degree.; 121
(.+-.)-3-(5'-1-Methylindolinyl)-5.beta.-(acetamidomethyl)
oxazolidin-2-one (XI), NMR (methanol-d.sub.4) 7.36, 7.08, 6.49,
4.70, 4.02, 3.71, 3.51, 3.25, 2.89, 2.71 and 1.96 .delta.; 122
(.+-.)-3-(5'-1-Hydroxyacetylindolinyl)-5.beta.-(acetamidomethyl)
oxazolidin-2-one (XI), mp 207-209.degree.; 123
(.+-.)-3-(5'-1-Benzyloxyacetylindolinyl)-5.beta.-(acetamidomethyl)
oxazolidin-2-one (XI), mp 181-183.degree.; 124
(.+-.)-3-(5'-1-p-Chlorobenzoylindolinyl)-5.beta.-(acetamidomethyl)
oxazolidin-2-one (XI), mp 225-227.degree.; 125
(.+-.)-3-(5'-1-Allylindolinyl)-5.beta.-(acetamidomethyl)oxazolidin-
2-one (XI), mp 152-153.degree.; 126
(.+-.)-3-(5'-1-Propylindolinyl)-5.beta.-(acetamidomethyl)
oxazolidin-2-one (XI), NMR (CDCl.sub.3, 300 MHz) 7.21, 7.17, 7.00,
6.37, 4.70, 3.99, 3.71, 3.56, 3.33, 2.95, 1.99, 1.60, and 0.97
.delta.; CMR (CDCl.sub.3, 75.47 MHz): 11.56, 20.37, 22.83, 28.41,
41.86, 48.80, 51.07, 53.02, 71.80, 106.29, 117.48, 119.47, 127.80,
130.85, 150.34, 155.33, and 171.259 .delta.; IR (mineral oil mull)
3418, 1732, 1661, 1550, 1504, 1473, 1228, and 1084 cm.sup.-1 ;MS
(m/e): 317, 288, 244, 185, 173, 159, and 130; exact mass calculated
for C.sub.17 H.sub.23 N.sub.3 O.sub.3 = 317.1739, found 317.1736.
127
(.+-.)-3-(5'-1-Methoxyacetylindolinyl)-5.beta.-(acetamidomethyl)
oxazolidin-2-one (XI), mp 209-210.degree.; 128
(.+-.)-3-(5'-1-Hexanoylindolinyl)-5.beta.-(acetamidomethyl)
oxazolidin-2-one (XI), mp 194-195.degree.. EX-
(.+-.)-3-(1'-Oxo-2'.alpha.-methyl-5'-indanyl)-5.beta.- AM-
(acetamidomethyl)oxazolidin-2-one (XXIB), (.+-.)-3-(1'- PLE
oxo-2'.beta.-methyl-5'-indanyl)-5.beta.-(acetamido-methyl) 129
oxazolidin-2-one (XXIB) and (.+-.)-3-(1'-Oxo-2',2'-
dimethyl-5'indanyl)-5.beta.-(acetamidomethyl)oxazolidin-2-one
(XXIB) ______________________________________
n-Butyl lithium (1.6M, 0.92 ml) is added to a solution of
diisopropylamine (20 ml) in dry tetrahydrofuran (15 ml) at
-78.degree. under nitrogen, and the mixture stirred for 30 min.
Solid
(.+-.)-3-(1'-oxo-5'-indanyl)-5.beta.-(acetamidomethyl)oxazolidin-2-one
(XXIB, EXAMPLE 52, 200 mg) is added at once, and the mixture is
stirred for 30 min at -78.degree., then iodomethane (48 .mu.l) of
iodomethane is added and the mixture then allowed to stir at
0.degree. for an additional 21 hr. The mixture is quenched with
saturated aqueous ammonium chloride (10 ml), and then poured into
water (30 ml), and the pH adjusted to 7. The aqueous layer is
extracted with ethyl acetate (4x), and the combined organic layers
are washed with saline, then dried over magnesium sulfate, and
concentrated under reduced pressure to give an residual oil. The
oil is purified by preparative TLC [2000 u, 20 cm.times. 20 cm,
methanol/ethyl acetate (4/96, 4 elutions)] to give the
.alpha./.beta.-methyl compounds, NMR (CDCl.sub.3) 7.72, 7.64, 7.52,
6.59, 4.84, 4.13, 3.89, 3.69, 3.38, 2.72, 2.04 and 1.30 .delta.;
CMR (CDCl.sub.3) 16.18, 22.85, 34.85, 41.61, 41.97, 47.43, 71.95,
114.75, 116.98, 124.77, 131.82, 143.39, 153.99, 154.81, 171.14 and
207.89 .delta.; IR (CHCl.sub.3) 3440, 1753, 1696, 1672 and 1603
cm.sup.-1 ; MS (m/e) 302, 258, 243, 230, 215 and 199; exact mass
calcd for C.sub.16 H.sub.18 N.sub.2 O.sub.4 =302.1267, found
302.1274 and the dimethyl compound, MS (m/e) 316, 272, 257, 244,
229, 213 and 43; exact mass calcd for C.sub.17 H.sub.20 N.sub.2
O.sub.4 =316.1423, found 316.1420.
EXAMPLE 130
(.+-.)-3-(1'-Oxo-2'.alpha.-ethyl-5'-indanyl)-5.beta.-(acetamidomethyl)oxazo
lidin-2-one (XXIB),
(.+-.)-3-(1'-oxo-2'.beta.-ethyl-5'-indanyl)-5.beta.-(acetamidomethyl)oxazo
lidin-2-one (XXIB) and
(.+-.)-3-(1'-Oxo-2',2'-diethyl-5'-indanyl)-5.beta.-(acetamidomethyl)oxazol
idin-2-one (XXIB)
Following the general procedure of EXAMPLE 129 and making
noncritical variations but using ethyl iodide (72 .mu.l), permiting
the mixture to warm to 20.degree.-25.degree. for 18 hr, and the
eluting with methanol/ethyl acetate (7/93)], the title compounds
are obtained, NMR (CDCl.sub.3) 7.74, 7.68, 7.51, 6.26, 4.83, 4.13,
3.87, 3.70, 3.30, 2.82, 2.64, 2.04, 1.96, 1.55 and 1.00 .delta.;
CMR (CDCl.sub.3) 75.47 MHz) 11.35, 22.98, 24.41, 32.28, 41.76,
47.51, 48.77, 71.89, 114.89, 116.98, 124.77, 132.6, 143.5, 154.1,
155.2, 171.1 and 207.5 .delta.; IR (CHCl.sub.3) 3680, 3440, 1750,
1680 and 1600 cm.sup.- ; MS (m/e) 316, 288, 272, 244, 229, 42,
exact mass calcd for C.sub.17 H.sub.20 N.sub.2 O.sub.4 =316.1423,
found 316.1412.
EXAMPLE 131
(.+-.)-3-(1'-Oxo-2'-spirocyclopropyl-5'-indanyl)-5.beta.-(acetamidomethyl)-
oxazolidin-2-one (XXIB)
Sodium hydride/mineral oil suspension is added (50%, 33 mg) to dry,
distilled t-butanol (5 ml) followed by
(35)-3-(1'-oxo-5'-indanyl)-5.beta.-(acetamidomethyl)oxazolidin-2-one
(XXIB, EXAMPLE 52, 100 mg). The mixture stirred at
20.degree.-25.degree. for 15 min. Then sodium iodide (10 mg) is
added, followed by 2-chloroethyldimethylsulfonium iodide (88 mg) in
small portions over a period of 1 hr, and the resulting mixture is
stirred for an additional 21 hr. Then water (25 ml) is added to the
mixture, and the pH adjusted to 7, and the mixture extracted with
ethyl acetate (4.times.). The combined organic layers are washed
with saline, dried over magnesium sulfate and concentrated under
reduced pressure to give an oily residue. The oil is purified by
preparative TLC [1000 micron, 20 cm.times.20 cm, methanol/ethyl
acetate (5/95), 3 elutions] to give the title compound, NMR
(CDCl.sub.3) 7.78, 7.77, 7.51, 6.11, 4.84, 4.14, 3.89, 3.68, 3.21,
2.03, 1.45 and 1.15 .delta..
EXAMPLE 132
(.+-.)-3-(1'-Oxo-2.alpha.-methyl-6'-tetralinyl)-5.beta.-(acetamidomethyl)ox
azolidin-2-one (XXIB), (.+-.)-3
-(1'-oxo-2'.beta.-methyl-6'-tetralinyl)-5-(acetamidomethyl)oxazolidin-2-on
e (XXIB) and
(.+-.)-3-(1'-Oxo-2',2'-dimethyl-6'tetralinyl)-5.beta.-(acetamidomethyl)oxa
zolidin-2-one (XXIB)
Following the general procedure of EXAMPLE 129 and making
non-critical variations but starting with
(.+-.)-3-(1'-oxo-6'-tetralinyl)-5.beta.-(acetamidomethyl)oxazolidin-2-one
(XXIB, EXAMPLE 56) the .alpha./.beta.-methyl compounds are
obtained, NMR (CDCl.sub.3) 8.03, 7.44, 7.40, 6.38, 4.81, 4.08,
3.84, 3.67, 2.98, 2.57, 2.18, 2.03, 1.90 and 1.26 .delta.; the
dimethyl compound, MS (m/e) 330, 286, 274, 258, 202 and 42; exact
mass calcd for C.sub.18 H.sub.22 N.sub.2 O.sub.4 =330.1580, found
330.1577.
EXAMPLE 133
(.+-.)-3-(1'-Oxo-2'-spirocyclopropyl-6'-tetralinyl)-5.beta.-(acetamidomethy
l)-oxazolidin-2-one (XXIB)
Following the general procedure of EXAMPLE 131 and making
non-critical variations but starting with
(.+-.)-3-(1'-oxo-6'-tetralinyl)-5.beta.-(acetamidomethyl)oxazolidin-2-one
(XXIB, EXAMPLE 56) the title compound is obtained, TLC
(methanol/ethyl acetate; 5/95) R.sub.f =0.32.
EXAMPLE 134
(.+-.)-3-(1'-Oxo-2'.alpha.-hydroxymethyl-5'-indanyl)-5.beta.-(acetamidometh
yl)-oxazolidin-2-one (XXIB) and
(.+-.)-3-(1'-oxo-2'.beta.-hydroxymethyl-5'-indanyl)-5.beta.-(acetamidometh
yl)oxazolidin-2-one (XXIB)
A sodium hydride/mineral oil dispersion (50%, 66 mg) is added all
at once to a solution of
(.+-.)-3-(1'-oxo-5'-indanyl)-5.beta.-(acetamidomethyl)oxazolidin-2-one
(XXIB, EXAMPLE 52, 200 mg) in dry tetrahydrofuran (5 ml) at
0.degree. and the mixture stirred for 30 min at 0.degree.. Then
excess gaseous formaldehyde is bubbled into the solution via a
needle attached to a flask where solid paraformaldehyde is heated.
The reaction mixture is then allowed to warm to
20.degree.-25.degree. for 1 hr and then poured into water and
extracted with ethyl acetate 3 times. The combined organic extracts
are combined, dried over magnesium sulfate and concentrated under
reduced pressure to give a solid. The solid is chromatographed on
silica gel (1000 .mu.) preparative TLC using a 20.times.20 cm
plate, and eluting with methanol/ethyl acetate (5/95) to give the
title compounds.
EXAMPLE 135
(.+-.)-3-(1'-Oxo-2'.alpha.-hydroxymethyl-6'-tetralinyl)-5.beta.-(acetamidom
ethyl)oxazolidin-2-one (XXIB) and
(.+-.)-3-(1'-oxo-2'-.beta.-hydroxymethyl-6'-tetralinyl)-5.beta.-(acetamido
methyl)oxazolidin-2-one (XXIB)
Following the general procedure of EXAMPLE 134 and making
non-critical variations but starting with
(.+-.)-3-(1'-oxo-6'-tetralinyl)-5.beta.-(acetamidomethyl)oxazolidin-2-one
(XXIB, EXAMPLE 56) the title compounds are obtained.
EXAMPLE 136
3-(1'-Oxo-2'.alpha.-methyl-5'-indanyl)-5.beta.-(acetamidomethyl)oxazolidin-
2-one
(XXIB),3-(1'-oxo-2'.beta.-methyl-5'-indanyl)-5.beta.-(acetamidomethyl)oxaz
olidin-2-one (XXIB) and
3-(1'-Oxo-2',2'-dimethyl-5'-indanyl)-5.beta.-(acetamidomethyl)oxazolidin-2
-one (XXIB)
Following the general procedure of EXAMPLE 129 and making
non-critical variations but starting with
3-(1'-oxo-5'-indanyl)-5.beta.-(acetamidomethyl)oxazolidin-2-one
(XXIB, EXAMPLE 108) the title compounds are obtained.
EXAMPLE 137
3-(1'-Oxo-2'.alpha.-ethyl-5'-indanyl)-5.beta.-(
acetamidomethyl)oxazolidin-2-one (XXIB) and
3-(1'-oxo-2'-.beta.-ethyl-5'-indanyl)-5.beta.-(acetamidomethyl)oxazolidin-
2-one (XXIB)
Following the general procedure of EXAMPLE 130 and making
non-critical variations but starting with
3-(1'-oxo-5'-indanyl)-5.beta.-(acetamidomethyl)oxazolidin-2-one
(XXIB, EXAMPLE 108) the title compounds are obtained.
EXAMPLE 138
3-(1'-Oxo-2'-spirocyclopropyl-5'-indanyl)-5.beta.-(acetamidomethyl)oxazolid
in-2-one (XXIB)
Following the general procedure of EXAMPLE 131 and making
non-critical variations but starting with
3-(1'-oxo-5'-indanyl)-5.beta.-(acetamidomethyl)oxazolidin-2-one
(XXIB, EXAMPLE 108), the title compound is obtained.
EXAMPLE 139
3-(1'-Oxo-2'.alpha.-methyl-6'-tetralinyl)5.beta.-(acetamidomethyl)oxazolidi
n-2-one (XXIB),
3-(1'-oxo-2'.beta.-methyl-6'-tetralinyl)-5.beta.-(acetamidomethyl)-oxazoli
din-2-one (XXIB) and
3-(1'-Oxo-2',2'-dimethyl-6'-tetralinyl)-5.beta.-(acetamidomethyl)oxazolidi
n-2-one (XXIB)
Following the general procedure of EXAMPLE 132 and making
non-critical variations but starting with
3-(1'-oxo-6'-tetralinyl)-5.beta.-(acetamidomethyl)oxazolidin-2-one
(XXIB, EXAMPLE 112), the title compounds are obtained.
EXAMPLE 140
3-(1'-Oxo-2'-spirocyclopropyl-6'-tetralinyl)-5.beta.-(acetamidomethyl)-oxaz
olidin-2-one (XXIB)
Following the general procedure of EXAMPLE 133 and making
non-critical variations but starting with
3-(1'-oxo-6'-tetralinyl)-5.beta.-(acetamidomethyl)oxazolidin-2-one
(XXIB, EXAMPLE 112), the title compound is obtained.
EXAMPLE 141
3-(1'-Oxo-2'.alpha.-hydroxymethyl-5'-indanyl)-5.beta.-(acetamidomethyl)-oxa
zolidin-2-one (XXIB) and
3-(1'-oxo-2'.beta.-hydroxymethyl-5'-indanyl)-5.beta.-(acetamidomethyl)oxaz
olidin-2-one (XXIB)
Following the general procedure of EXAMPLE 134 and making
non-critical variations but starting with
3-(1'-oxo-5'-indanyl)-5.beta.-(acetamidomethyl)oxazolidin-2-one
(XXIB, EXAMPLE 108), the title compounds are obtained.
EXAMPLE 142
3-(1'-Oxo-2'.alpha.-hydroxymethyl-6'-tetralinyl)-5.beta.-(acetamidomethyl)o
xazolidin-2-one (XXIB) and
3-(1-oxo-2'.beta.-hydroxymethyl-6'-tetralinyl)-5.beta.-(acetamidomethyl)ox
azolidin-2-one (XXIB)
Following the general procedure of EXAMPLE 135 and making
non-critical variations but starting with
3-(1'-oxo-6'-tetralinyl)-5.beta.-(acetamidomethyl)oxazolidin-2-one
(XXIB, EXAMPLE 112), the title compounds are obtained.
EXAMPLE 143
(.+-.)-3-(5'-1-(O-Acetyl)hydroxyacetyl)indolinyl))-5-(acetamidomethyl)-oxaz
olidin-2-one (XI)
The free hydroxy group of
(.+-.)-3-(5'-1-hydroxyacetylindolinyl)-5-(acetamidomethyl)oxazolidin-2-one
(XI, EXAMPLE 122) is acylated as is know to those skilled in the
art, NMR (CDCl.sub.3, 300 MHz) 8.10, 7.58, 7.01, 6.49, 4.77, 4.01,
3.76, 3.65, 3.23, 2.23 and 2.04 .delta..
EXAMPLE 144
3-(5'-1-(O-Acetyl(hydroxyacetyl)indolinyl)-5.beta.-(acetamidomethyl)oxazoli
din-2-one (XI)
Following the general procedure of EXAMPLE 143 and making
non-critical variations but starting with
3-(5'-1-hydroxyacetylindolinyl)-5.beta.-(acetamidomethyl)oxazolidin-2-one
(XI, EXAMPLE 150) the title compound is obtained.
EXAMPLE 145
(.+-.)-3-[5'-1)(2-thienylcarbonyl)indolinyl]-5-(acetamidomethyl)oxazolidin-
2-one (XI)
Following the general procedure of EXAMPLE 18 and making
non-critical variations but using 2-thienylcarbonyl chloride, the
title compound is obtained, mp 201.degree.-203.degree..
EXAMPLE 146
3-[5'-1-(2-Thienylcarbonyl)indolinyl]5.beta.-(acetamidomethyl)oxazolidin-2-
one (XI)
Following the general procedure of EXAMPLE 18 and making
non-critical variations but using
3-(5'-indolinyl)-5.beta.-(acetamidomethyl)oxazolidin-2-one (X,
EXAMPLE 97) and 2-thienylcarbonyl chloride, the title compound is
obtained.
EXAMPLES 147-156
Following the general procedure of EXAMPLES 119-128 and making
non-critical variations but using the process of EXAMPLE 76 for the
resolution of the optically impure mixture of (VIII) and thereafter
using the optically active (VIII), the title compounds are
obtained:
______________________________________ 147
3-(5'-1-Benzoylindolinyl)-5.beta.-(acetamidomethyl)oxazolidin-
2-one (XI), 148
3-(5'-1-Methylsulfonylindolinyl)-5.beta.-(acetamidomethyl)
oxazolidin-2-one (XI), 149
3-(5'-1-Methylindolinyl-5.beta.-(acetamidomethyl)oxazolidin- 2-one
(XI), 150 3-(5'-1-Hydroxyacetylindolinyl)-5.beta.-(acetamidomethyl)
oxazolidin-2-one (XI), 151
3-(5'-1-Benzyloxyacetylindolinyl)-5.beta.-(acetamidomethyl)
oxazolidin-2-one (XI), 152
3-(5'-1-p-Chlorobenzoylindolinyl)-5.beta.-(acetamidomethyl)
oxazolidin-2-one (XI), 153
3-(5'-1-Allylindolinyl)-5.beta.-(acetamidomethyl)oxazolidin-2- one
(XI), 154
3-(5'-1-Propylindolinyl)-5.beta.-(acetamidomethyl)oxazolidin-2- one
(XI), 155 3-(5'-1-Methoxyacetylindolinyl)-5.beta.-(acetamidomethyl)
oxazolidin-2-one (XI), 156
3-(5'-1-Hexanoylindolinyl)-5.beta.-(acetamidomethyl)oxazolidin-
2-one (XI). ______________________________________ ##STR1##
Fused cycloalkylphenyl-oxazolidinones (XXIA) where one of R.sub.2
and R.sub.4 is --H and R.sub.2 or R.sub.3 end is: R.sub.3 or
R.sub.4 end is: --CH.sub.2 --CH.sub.2 --CH.sub.2 -- and --CH.sub.2
CH.sub.2 --CH.sub.2 --CH.sub.2 -- which is represented by
--(CH.sub.2).sub.n2-- where n.sub.2 is 3 or 4.
Fused alkanonephenyl-oxazolidinones (XXIB) where one of R.sub.2 and
R.sub.4 is --H and R.sub.2 or R.sub.3 end is: R.sub.3 or R.sub.4
end is: --CH.sub.2 --CHR.sub.10 --CO--, --CH.sub.2 --CH.sub.2
--CHR.sub.10 --CO--, --CH.sub.2 CHR.sub.10 --CO--CH.sub.2 --,
--CHR.sub.10 --CO--CH.sub.2 --, --CHR.sub.10 CO--CH.sub.2
--CH.sub.2 --, --CH.sub.2 --CO--CHR.sub.10 --, --CH.sub.2
--CH.sub.2 --CO--CHR.sub.10 --, --CH.sub.2 CO--CHR.sub.10
--CH.sub.2 --, --CO--CHR.sub.10 --CH.sub.2 -- and --CO--CHR.sub.10
--CH.sub.2 --CH.sub.2 -- which is represented by
--(CH.sub.2).sub.n3 --(CR.sub.10-1 R.sub.10-2).sub.n7
--CO--(CHR.sub.10-3 R.sub.10-4).sub.n8 --(CH.sub.2).sub.n4 --
where n.sub.3 and n.sub.4 are 0-3, and n.sub.7 and n.sub.8 are 0 or
1, R.sub.10-1 and R.sub.10-2 are the same or different and are --H,
C.sub.1 -C.sub.3 alkyl and where R.sub.10-1 and R.sub.10-2 taken
together with the carbon atom to which they are attached form
spirocyclopropyl, R.sub.10-3 and R.sub.10-4 are the same or
different and are --H, C.sub.1 -C.sub.3 alkyl and where R.sub.10-3
and R.sub.10-4 taken together with the carbon atom to which they
are attached form spirocyclopropyl, with the provisos that (1)
n.sub.7 +n.sub.8 =0 or 1, (2) n.sub.3 +n.sub.4 +n.sub.7 +n.sub.8 =2
or 3 and (3) when n.sub.4 is 0, either (a) n.sub.8 =1 or (b)
n.sub.7 =1 and one of R.sub.10-1 or R.sub.10-2 is not --H;
Fused hydroxycycloalkylphenyl-oxazolidinones (XXIC) where one of
R.sub.2 and R.sub.4 is --H and R.sub.2 or R.sub.3 end is: R.sub.3
or R.sub.4 end is: --CHOH--CH.sub.2 --CH.sub.2 --, --CH.sub.2
--CHOH--CH.sub.2 --, --CH.sub.2 --CH.sub.2 CHOH--, --CHOH--CH.sub.2
--CH.sub.2 --CH.sub.2 --, --CH.sub.2 CHOH--CH.sub.2 --CH.sub.2 --,
--CH.sub.2 --CH.sub.2 CHOH--CH.sub.2 -- and --CH.sub.2 --CH.sub.2
--CH.sub.2 --CHOH-- which is represented by --CH.sub.2).sub.n3
--CHOH--(CH.sub.2).sub.n4 -- where n.sub.3 and n.sub.4 are 0-3 with
the proviso that n.sub.3 +n.sub.4 =2 or 3.
Fused cycloalkenylphenyl-oxazolidinones (XXID) where one of R.sub.2
and R.sub.4 is --H and R.sub.2 or R.sub.3 end is: R.sub.3 or
R.sub.4 end is: --CH.dbd.CH--CH.sub.2 --, --CH.sub.2 --CH.dbd.CH--,
--CH.dbd.CH--CH.sub.2 --CH.sub.2 --, --CH.sub.2 CH.dbd.CH--CH.sub.2
-- and --CH.sub.2 --CH.sub.2 CH.dbd.CH-- which is represented by
--(CH.sub.2).sub.n5 --CH.dbd.CH--(CH.sub.2).sub.n6 -- where n.sub.5
and n.sub.6 are 0-2 with the proviso that n.sub.5 +n.sub.6 =1 or
2.
Fused oximinocycloalkylphenyl-oxazolidinones (XXIE) where one of
R.sub.2 and R.sub.4 is --H and R.sub.2 or R.sub.3 end is: R.sub.3
or R.sub.4 end is: --C(.dbd.N--OR.sub.7)--CHR.sub.10 --CH.sub.2 --,
--CHR.sub.10 --C(.dbd.N--OR.sub.7)--CH.sub.2 --, --CH.sub.2
--C(.dbd.N--OR.sub.7)--CHR.sub.10 --, --CH.sub.2 --CHR.sub.10
--C(.dbd.N--OR.sub.7)--, --C(.dbd.N--OR.sub.7)--CHR.sub.10
--CH.sub.2 --CH.sub.2 --, --CHR.sub.10
--C(.dbd.N--OR.sub.7)--CH.sub.2 --CH.sub.2 --, --CH.sub.2
C(.dbd.N--OR.sub.7)--CHR.sub.10 --CH.sub.2 --, --CH.sub.2
--CH.sub.2 CHR.sub.10 --C(.dbd.N--OR.sub.7)-- which is represented
by --(CH.sub.2).sub.n3 --CHR.sub.10).sub.n7
--C(.dbd.N--OR.sub.7)--(CHR.sub.10).sub.n8 --(CH.sub.2).sub.n4 --
where n.sub.3, n.sub.4, n.sub.7 and n.sub.8 are as defined above,
with the provisos that (1) n.sub.7 +n.sub.8 =0 or 1, (2) n.sub.3
+n.sub.4 +n.sub.7 +n.sub.8 =2 or 3 and (3) when n.sub.3 is 0,
either (a) n.sub.7 =1 or (b) n.sub.8 =1 and one of R.sub.10-1 or
R.sub.10-2 is not --H;
Fused iminocycloalkylphenyl-oxazolidinones (XXIF) where one of
R.sub.2 and R.sub.4 is --H and R.sub.2 or R.sub.3 end is: R.sub.3
or R.sub.4 end is: --C(.dbd.N--R.sub.8)--CH.sub.2 --CH.sub.2 --,
--CH.sub.2 --C(.dbd.N--R.sub.8)--CH.sub.2 --, --CH.sub.2 --CH.sub.2
--C(.dbd.N--R.sub.8)--, --C(.dbd.N--R.sub.8)--CH.sub.2 --CH.sub.2
--CH.sub.2 --, --CH.sub.2 C(.dbd.N--R.sub.8)--CH.sub.2 --CH.sub.2
--, --CH.sub.2 --CH.sub.2 --C(.dbd.N--R.sub.8)--CH.sub.2 --,
--CH.sub.2 --CH.sub.2 --CH.sub.2 --C(.dbd.N--R.sub.8)-- which is
represented by-(CH.sub.2).sub.n3
--C(.dbd.N--R.sub.8)--CH.sub.2).sub.n4 --where n.sub.3 and n.sub.4
are as defined above.
Fused aminocycloalkylphenyl-oxazolidinones (XXIG) where one of
R.sub.2 and R.sub.4 is --H and R.sub.2 or R.sub.3 end is: R.sub.3
or R.sub.4 end is: --C(NR.sub.11 R.sub.12)--CH.sub.2 --CH.sub.2 --,
--CH.sub.2 --C(NR.sub.11 R.sub.12)--CH.sub.2 --, --CH.sub.2
CH.sub.2 --C(NR.sub.11 R.sub.12)--, --C(NR.sub.11
R.sub.12)--CH.sub.2 --CH.sub.2 --CH.sub.2 --, --CH.sub.2
C(NR.sub.11 R.sub.12)--CH.sub.2 --CH.sub.2 --, --CH.sub.2 CH.sub.2
--C(NR.sub.11 R.sub.12)--CH.sub.2 --, --CH.sub.2 CH.sub.2 CH.sub.2
--(NR.sub.11 R.sub.12)-- which is represented by-(CH.sub.2).sub.n3
--CH(NR.sub.11 R.sub.12)--(CH.sub.2).sub.n4 -- where n.sub.3 and
n.sub.4 are as defined above.
Fused enaminocycloalkylphenyl-oxazolidinones (XXIH) where one of
R.sub.2 and R.sub.4 is --H and R.sub.2 or R.sub.3 end is: R.sub.3
or R.sub.4 end is: --C(NR.sub.13 R.sub.14).dbd.CH--CH.sub.2 --
--CH.dbd.C(NR.sub.13 R.sub.14)--CH.sub.2 -- --CH.sub.2
--C(NR.sub.13 R.sub.14).dbd.CH-- --CH.sub.2 CH.dbd.C(NR.sub.13
R.sub.14)-- --C(NR.sub.13 R.sub.14).dbd.CH--CH.sub.2 --CH.sub.2 --
--CH.dbd.C(NR.sub.13 R.sub.14)--CH.sub.2 --CH.sub.2 -- --CH.sub.2
C(NR.sub.13 R.sub.14).dbd.CH--CH.sub.2 -- --CH.sub.2
--CH.dbd.C(NR.sub.13 R.sub.14)--CH.sub.2 -- --CH.sub.2 --CH.sub.2
C(NR.sub.13 R.sub.14).dbd.CH-- --CH.sub.2 CH.sub.2
CH.dbd.C(NR.sub.13 R.sub.14)-- which is represented by
--(CH.sub.2).sub.n3 --CH.dbd.C(NR.sub.13
R.sub.14)--(CH.sub.2).sub.n4 -- where n.sub.3 and n.sub.4 are as
defined above. ##STR2##
Chart H
3-(nitrogen
substituted)phenyl-5.beta.-(amidomethyl)oxazolidin-2-ones (LV)
##STR3## includes: indazolyloxazolidin-2-ones (XXXII)
where W.sub.1 end is W.sub.2 end is ----NR.sub.5 --N.dbd.CR.sub.6
-- benzimidazolyloxazolidin-2-ones (XLIII)
where W.sub.1 end is W.sub.2 end is ----NR.sub.5 --CR.sub.6
.dbd.N-- benzotriazolyloxazolidin-2-ones (LIV)
where W.sub.1 end is W.sub.2 end is --NR.sub.5 --N.dbd.N--
* * * * *